HIV protease inhibitors

ABSTRACT

Compounds useful for inhibiting HIV protease are disclosed. Methods of making the compounds, and their use as therapeutic agents, for example, in treating wild-type HIV and of multidrug-resistant strains of HIV, also are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional U.S. PatentApplication Ser. No. 60/363,628, filed Mar. 12, 2002 and provisionalU.S. Patent Application Ser. No. 60/433,627, filed Dec. 13, 2002.

STATEMENT OF GOVERNMENTAL INTEREST

This invention was made with Government support under contract GM53386awarded by the National Institutes of Health. The Government has certainrights in this invention.

FIELD OF THE INVENTION

The present invention relates to compounds useful for inhibiting HIVprotease enzymes. More particularly, the present invention relates toHIV protease inhibitors, methods of manufacturing the inhibitors, andtheir use as therapeutic agents, for example, in treating wild-type HIVand multidrug-resistant strains of HIV.

BACKGROUND OF THE INVENTION

It is well known that a wide range of diseases are caused byretroviruses As presently understood, acquired immunodeficiency syndrome(AIDS) is a disease of the immune system caused by the retrovirus HIV(Human Immunodeficiency Virus). According to estimates from the WorldHealth Organization, AIDS affects millions of people and is continuingto spread. In virtually all cases, AIDS results in death of the infectedindividual.

Retroviruses HIV-1 and HIV-2 have been identified as a cause of AIDS. Aretroviral protease is a proteolytic enzyme that participates in thematuration of new infectious virions in infected cells during thereproductive cycle. In a number of retroviruses, for example, HIV-1 andHIV-2, each have a region in their genome that codes for a“gag-protease.” The “gag-protease” is responsible for the correctproteolytic cleavage of the precursor proteins that are produced fromthe genome regions coding for the “Group Specific Antigens” (gag).

The “gag-protease” cleaves the major core protein p24 of HIV-1 and HIV-2preferentially N-terminally of proline residues, for example, in thedivalent residues Phe-Pro, Leu-Pro, or Tyr-Pro. It is a protease havinga catalytically active aspartate residue in the active center, i.e., anaspartate protease. During cleavage, the structural proteins of thevirus core are liberated. The “gag-protease” itself is a component of aprecursor protein encoded by the pol-genome region of HIV-1 and HIV-2,which also contain regions for the “reverse transcriptase” and“integrase” and is thought to be cleaved by autoproteolysis.

Retroviral protease is a critical enzyme in the retroviral replicationprocess. Propagation of a retrovirus, such as HIV, can be impeded byexposing the virus to a retroviral protease inhibitor. As used herein,protease inhibitor refers to compounds that inhibit proteases of viralorigin, and that are useful in the prophylaxis or treatment of viralinfections caused by retroviruses, such as HIV, in mammals, both humanand nonhuman. Protease inhibitors perform at the final stage of viralreplication, and prevent HIV from making new copies of itself byinterfering with the HIV protease enzyme. As a result, the new copies ofHIV are not able to infect new cells.

Retroviral protease inhibition typically involves a transition-statemimetic whereby the retroviral protease is exposed to a compound thatbinds, typically in a reversible manner, to the enzyme in competitionwith the gag and gag-pol proteins to inhibit specific processing ofstructural proteins and the release of retroviral protease itself. Inthis manner, retroviral replication proteases can be effectivelyinhibited.

Several classes of compounds for inhibition of proteases, including HIVprotease, have been proposed. Such compounds include hydroxyethylamineisosteres, reduced amide isosteres, and nonpeptide isosteres. See, forexample, EP 0 346 847; EP 0 342 541; Roberts et al., “Rational Design ofPeptide-Based Proteinase Inhibitors,” Science, 248, 358 (1990); Ericksonet al., “Design Activity, and 2.8 Å Crystal Structure of a C2 SymmetricInhibitor Complexed to HIV-1 Protease,” Science, 249, 527 (1990); and S.Thaisrivongs, “Structure-Based Design of Non-Peptide HIV ProteaseInhibitors,” 35th Annual Buffalo Medicinal Chemistry Meeting, StateUniversity of New York at Buffalo, Buffalo, N.Y., May, 1994. Also, see,for example, U.S. Pat. Nos. 6,008,228; 6,100,277; and 6,245,806.

Some antiviral compounds that act as inhibitors of HIV replication areeffective agents in the treatment of AIDS and similar diseases, e.g.,azidothymidine or AZT. WO 99/67254 contains a discussion of AIDS and HIVprotease inhibitors, and is incorporated herein by reference. However, atypical problem associated with retroviral protease inhibitors, like HIVprotease inhibitors, has been the development of strains of the virusresistant to the inhibitor. The present invention provides nonpeptidiccompounds that are effective inhibitors of HIV protease, and are usefulin the treatment of AIDS or HIV infections, includingmultidrug-resistant strains of HIV.

SUMMARY OF THE INVENTION

The present invention is directed to a novel class of highly potent HIVprotease inhibitors. This class of compounds is useful in the treatmentof HIV infection. Protease inhibitors of this new class of compoundshave been synthesized and tested for efficacy.

Compounds of the present invention have a general structural formula(I):

These compounds include, but are not limited to, those having thefollowing structural components: (a) compounds containing a lactam atR³, including 5-, 6-, and 7-membered lactams; (b) compounds containingan extension of the R³ lactam via a fused or spirocyclic ring system,especially systems containing basic amine substituents and hydroxymethylsubstituents for increased binding affinity for HIV protease; (c)compounds containing various R² groups, including isobutyl, lactams,urethanes, furans, pyrans, pyrrolidines, and piperidines, as well asfused or spirocyclic ring systems extending from the above-mentionedmoieties at the R² position; (d) compounds having an R¹ group such asbistetrahydrofuran or a fused cyclopentyl tetrahydrofuran, as well asother bicyclic ring systems disclosed herein. A judicious selection ofR¹, R², R³, and R⁴ groups provides compounds having excellent inhibitorproperties including in vitro potency, in vivo potency, and oralbioavailability.

One aspect of the present invention is to provide compounds having astructural formula (I)

wherein R¹ is selected from the group consisting of C₁₋₆alkyl, aryl,C₁₋₃alkyleneheteroaryl,

R² is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneN(R^(e))₂, heterocycloalkyl, —NH₂, —NHBoc,C₁₋₃alkyleneheterocycloalkyl,

optionally substituted with oxo(═O),

optionally substituted with oxo,

optionally substituted with oxo,

R³ is selected from the group consisting of

or R² and R³ are taken together to form either an optionally substitutedmonocyclic or bicyclic aliphatic ring system, or an optionallysubstituted macrocyclic ring system containing twelve to twenty atoms,including one to three heteroatoms selected from oxygen, nitrogen, andsulfur;

R⁴ is selected from the group consisting of hydro andC₁₋₃alkyleneheterocycloalkyl optionally substituted with C(═O)aryl orC₁₋₃alkylenearyl;

X is selected from the group consisting of O, NR^(e), S, SO, and SO₂;

A and B, independently, are a five-, six-, or seven-membered aliphaticring, wherein at least one ring contains one or two of the moiety X;

C is a five- or six-membered aliphatic ring containing one to three ofthe moiety X, and optionally substituted with oxo;

R^(a) is a five- or six-membered aliphatic ring containing one or two ofthe moiety X;

R^(b) and R^(c), independently, are selected from the group consistingof hydro, OH, C₁₋₃alkyl, C₁₋₃alkyleneOH, and C₁₋₃alkyleneN(R^(e))₂, orR^(b) and R^(c) are taken together to form a five-, six-, orseven-membered aliphatic ring optionally containing one or two of themoiety X;

R^(d) is selected from the group consisting of C₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneC₃₋₈heterocycloalkyl, OR^(e), C₁₋₃alkyleneOR^(e), N(R^(e))₂,SR^(e), halo, nitro, CHO, cyano, NC, C(═O)R^(e), OC(═O)R^(e),C(═O)OR^(e), C(═O)—N(R^(e))₂, CH═NOH, CH═CHCH₂OH, N(R^(e))COR^(e), andC₁₋₃alkyleneN(R^(e))₂, or two R^(d) groups are taken together to form afive-, six-, or seven-membered aliphatic ring optionally containing oneor two of the moiety X;

R^(e) is selected from the group consisting of hydro, C₁₋₆alkyl,C₂₋₆alkenyl, aryl, heteroaryl, C₃₋₈cycloalkyl, THP, Ts, Boc, andC₃₋₈heterocycloalkyl;

q is 0 through 3;

and pharmaceutically acceptable salts, prodrugs, or solvates thereof.

Another aspect of the present invention is to provide a potent HIVprotease inhibitor useful in the treatment of HIV and AIDS, particularlyin the treatment of wild-type HIV and multidrug-resistant strains ofHIV. The compounds of structural formula (I) have demonstratedsignificant HIV protease inhibition activity.

Another aspect of the present invention is to provide a method oftreating mammalian HIV infections using a retroviral protease inhibitorwhich is effective in preventing the replication of retroviruses invitro or in vivo. A present protease inhibitor can be used alone, or incombination with (a) a second protease inhibitor, (b) another antiviralagent, or (c) both (a) and (b).

Still another aspect of the present invention is to providepharmaceutical compositions containing one or more compounds ofstructural formula (I), to use of the compounds and compositionscontaining the compounds in the therapeutic treatment of a disease ordisorder, and to methods of preparing the compounds of structuralformula (I) and intermediates involved in the synthesis thereof.

Yet another aspect of the present invention is to provide a method ofinhibiting the protease of a multidrug-resistant retrovirus in a mammalinfected with the retrovirus, said method comprising administering atherapeutically effective amount of one or more compounds of structuralformula (I) to the mammal to inhibit proliferation of the retrovirus.

Another aspect of the present invention is to provide a kit for thetreatment of HIV or AIDS comprising a compound of structural formula(I), or a composition containing the same, packaged with instructionsfor administration of the compound or composition to treat HIV or AIDS.

Yet another aspect of the present invention is to provide an article ofmanufacture for human pharmaceutical use, comprising (a) a packageinsert, (b) a container, and either (c1) a packaged compositioncomprising a compound of structural formula (I) and a secondpharmaceutical drug or (c2) a packaged composition comprising a compoundof structural formula (I) and a packaged composition comprising a secondpharmaceutical drug. The second pharmaceutical drug typically is usefulin the treatment of HIV or AIDS.

The above and other aspects and advantages of the present invention areset forth in the following detailed description of the preferredembodiments.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Retroviral protease is a critical enzyme in the retroviral replicationprocess. Propagation of a retrovirus, such as HIV, can be impeded byexposing the virus to a retroviral protease inhibitor. The presentinvention is directed to compounds of structural formula (I), theinhibition of HIV protease, the prevention or treatment of infection byHIV, and the treatment of AIDS. In particular, the present invention isdirected to compounds that treat multidrug-resistant strains of HIV.

Several protease inhibitors currently are available commercially,including saquinavir (also known as INVIRASE®, FORTOVASE®, andRo31-8959), nelfinavir (also known as VIRACEPT®), amprenavir (also knownas AGENERASE®, VX-478, and 141W94), indinavir (also known as CRIXIVAN®,L-735,524, and MK-639), ritonavir (also known as NORVIR®, and ABT-538),and lopinavir (also known as ALUVIRAN® and ABT-378). All of the abovecompounds suffer from an inability to treat multidrug-resistant strainsof HIV.

The compounds of structural formula (I) are defined as follows:

wherein R¹ is selected from the group consisting of C₁₋₆alkyl, aryl,C₁₋₃alkyleneheteroaryl,

R² is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneN(R^(e))₂, heterocycloalkyl, NH₂, NHBoc,C₁₋₃alkyleneheterocycloalkyl,

optionally substituted with oxo(═O),

optionally substituted with oxo,

optionally substituted with oxo,

R³ is selected from the group consisting of

or R² and R³ are taken together to form either an optionally substitutedmonocyclic or bicyclic aliphatic ring system, or an optionallysubstituted macrocyclic ring system containing twelve to twenty atoms,including one to three heteroatoms selected from oxygen, nitrogen, andsulfur;

R⁴ is selected from the group consisting of hydro andC₁₋₃alkyleneheterocycloalkyl optionally substituted with C(═O)aryl orC₁₋₃alkylenearyl;

X is selected from the group consisting of O, NR^(e), and S; SO, andSO₂;

A and B, independently, are five-, six-, or seven-membered aliphaticring, wherein at least one ring contains one or two of the moiety X;

C is a five- or six-membered aliphatic ring containing one to three ofthe moiety X, and optionally substituted with oxo;

R^(a) is a five- or six-membered aliphatic ring containing one or two ofthe moiety X;

R^(b) and R^(c), independently, are selected from the group consistingof hydro, OH, C₁₋₃alkyl, C₁₋₃alkyleneOH, and C₁₋₃alkyleneN(R^(e))₂, orR^(b) and R^(c) are taken together to form a five-, six-, orseven-membered aliphatic ring optionally containing one or two of themoiety X;

R^(d) is selected from the group consisting of C₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneC₃₋₈heterocycloalkyl, OR^(e), C₁₋₃alkyleneOR^(e), N(R^(e))₂,SR^(e), halo, nitro, CHO, cyano, NC, C(═O)R^(e), OC(═O)R^(e),C(═O)OR^(e), C(═O)—N(R^(e))₂, CH═NOH, CH═CHCH₂OH, N(R^(e))COR^(e), andC₁₋₃alkyleneN(R^(e))₂, or two R^(d) groups are taken together to form afive-, six-, or seven-membered aliphatic ring optionally containing oneor two of the moiety X;

R^(e) is selected from the group consisting of hydro, C₁₋₆alkyl,C₂₋₆alkenyl, aryl, heteroaryl, C₃₋₈cycloalkyl, THP, Ts, Boc, andC₃₋₈heterocycloalkyl;

q is 0 through 3;

and pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also is directed to pharmaceutical compositionsuseful for inhibiting HIV protease, said compositions comprising acompound of structural formula (I) and a pharmaceutically acceptablecarrier. These pharmaceutical compositions are useful for treatinginfection by HIV, or for treating AIDS or ARC. The present inventionalso is directed to methods of inhibiting HIV protease, methods oftreating infection by HIV, and methods of treating AIDS or ARCcomprising administration of a therapeutically effective amount of acompound of structural formula (I) or a composition containing acompound of structural formula (I) to an individual in need thereof.

Additionally, the present invention is directed to a pharmaceuticalcomposition comprising a compound of structural formula (I) and an AIDStreatment agent selected from the group consisting of (a) an AIDSantiviral agent, (b) an antiinfective agent, (c) an immunomodulator, and(d) mixtures thereof. The compound of structural formula (I) and theAIDS treatment agent can be packaged separately or together, andadministered simultaneously or sequentially.

In preferred embodiments of a compound of structural formula (I), R¹ isselected from the group consisting of

R² is selected from the group consisting of —CH₂CH(CH₃)₂, —NH₂, —NHBoc,—(CH₂)₃CH═CH₂, —(CH₂)₄—CH═CH₂,

R³ is selected from the group consisting of

or R² and R³ are taken together, with the nitrogen atom to which theyare attached, to form

optionally substituted with C(═O)NHC₁₋₆alkyl, or a macrocyclic ringsystem containing 16 to 20 carbon atoms, optionally including SO₂,oxygen atoms, or both, and optionally substituted with one or morephenyl, benzyl, oxo(═O), and OR^(e);

R⁴ is hydro;

R^(b) and R^(c), independently, are hydro or C₁₋₃alkyl, or are takentogether to form (—CH₂—)₄.

and R^(d) is selected from the group consisting of C₁₋₃alkyleneOR^(e),N(R^(e))₂, C₁₋₃alkyl, halo, nitro, C₁₋₃alkyleneC₃₋₈heterocycloalkyl,CHO, CH═NOH, and OR^(e), or two R^(d) groups are taken together with thecarbons to which they are attached to form

As used herein, the term “alkyl” includes straight chained and branchedhydrocarbon groups containing the indicated number of carbon atoms. Thehydrocarbon group can contain 1 to 20 carbon atoms, typically methyl,ethyl, and straight-chain and branched propyl and butyl groups. The term“alkyl” includes “bridged alkyl,” i.e., a C₆₋₁₆ bicyclic or polycyclichydrocarbon group, for example, norbornyl, adamantyl,bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, ordecahydronaphthyl. Alkyl groups can be substituted, for example, withhydroxy (OH), halogen, aryl, heteroaryl, heterocycloalkyl, amino(N(R^(e))₂) groups, and sulfonyl (SO₂R^(e)) groups.

The term “alkenyl” is defined similarly as alkyl, except an alkenylgroup contains at least one carbon-carbon double bond.

The term “alkylene” is defined as an alkyl group having a substituent.For example, the term “C₁₋₃alkyleneOH” refers to an alkyl groupcontaining one to three carbon atoms and substituted with a hydroxygroup.

The term “cycloalkyl” is defined as a cyclic C₃₋₈ hydrocarbon group,e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl.“Heterocycloalkyl” is defined similarly as cycloalkyl except the ringcontains one to three heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur. Cycloalkyl and heterocycloalkyl groups canbe saturated or partially unsaturated ring systems substituted with, forexample, one to three groups, independently selected from C₁₋₄alkyl,C₁₋₃alkyleneOH, C(═O)NH₂, NH₂, oxo(═O), aryl, trifluoroethanoyl, and OH.

The term “macrocyclic” is defined as an optionally substituted ringsystem containing ten to twenty atoms, optionally including up to fourheteroatoms selected from oxygen, sulfur, SO, SO₂, and N(R^(e)). Atomspresent in an aryl or heteroaryl ring can contribute to the atoms of themacrocyclic ring.

The term “halo” or “halogen” is defined herein to include fluorine,bromine, chlorine, and iodine.

The term “aryl,” alone or in combination, is defined as a monocyclic orpolycyclic aromatic group, preferably a monocyclic or bicyclic aromaticgroup, e.g., phenyl or naphthyl. Unless otherwise indicated, an “aryl”group can be unsubstituted or substituted, for example, with one ormore, and in particular one to four, halo, CH═NOH, C₁₋₆alkyl,C₂₋₆alkenyl, OCF₃, NO₂, CN, NC, N(R)₂, OR, CO₂R, C(O)N(R)₂, C(O)R,N(R^(a))COR^(b), N(R^(a))C(O)OR, C₁₋₃alkyleneOR, and SR, wherein R isselected from the group consisting of hydro, C₁₋₆alkyl, C₂₋₆alkenyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, SO₂R^(e), OTs, NHBoc,OTHP, and C₁₋₆alkyl substituted with halo, hydroxy, aryl, heteroaryl,heterocycloalkyl, N(R^(e))₂, or SO₂R^(e), and R^(e) is as previouslydefined. Exemplary aryl groups include phenyl, naphthyl,tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl,trifluoromethylphenyl, nitrophenyl, hydroxyphenyl, and the like. Theterms “arylC₁₋₃alkyl” and “heteroarylC₁₋₃alkyl” are defined as an arylor heteroaryl group having a C₁₋₃alkyl substituent.

The term “heteroaryl” is defined herein as a monocyclic or bicyclic ringsystem containing one or two aromatic rings and containing at least onenitrogen, oxygen, or sulfur atom in an aromatic ring, and which can beunsubstituted or substituted, for example, with one or more, and inparticular one to four, substituents, for example, hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, aryl, N(R^(e))₂, OR^(e), and halo, wherein R^(e) is aspreviously defined. Examples of heteroaryl groups include, but are notlimited to, thienyl, furyl, pyridyl, oxazolyl, quinolyl, isoquinolyl,indolyl, triazolyl, isothiazolyl, isoxazolyl, imidizolyl,benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

The term “hydroxy” is defined as —OH.

The term “Boc” is defined as t-butoxycarbonyl.

The term “THP” is defined as tetrahydropyranyl.

The term “Ts” is defined as p-toluenesulfonyl or tosyl.

The carbon atom content of hydrocarbon-containing moieties is indicatedby a subscript designating the minimum and maximum number of carbonatoms in the moiety, e.g., “C₁₋₆alkyl” refers to an alkyl group havingone to six carbon atoms, inclusive.

The term “Me” is methyl (CH₃), “Et” is ethyl (C₂H₅), and “Ph” is phenyl(C₆H₅).

In the structures herein, for a bond lacking a substituent, thesubstituent is methyl, for example,

When no substituent is indicated as attached to a carbon atom on a ring;it is understood that the carbon atom contains the appropriate number ofhydrogen atoms. In addition, when no substituent is indicated asattached to a carbonyl group or a nitrogen atom, for example, thesubstituent is understood to be hydrogen, e.g.,

The notation

and similar notations mean that the ring system is attached to theremainder of the compound via any atom of the A or B ring.

The notation N(R^(x))₂, wherein x represents an alpha or numericcharacter, such as, for example, R^(a), R^(b), R¹, R², and the like, isused to denote two R^(x) groups attached to a common nitrogen atom. Whenused in such notation, the R^(x) group can be the same or different, andis selected from the group as defined by the R^(x) group.

The present invention also is directed to pharmaceutical compositionscontaining one or more compounds of structural formula (I), to use ofthe compounds and compositions containing the compounds in therapeutictreatment of a disease or disorder, and to methods of preparing thecompounds and intermediates involved in the synthesis of the compoundsof structural formula (I).

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results directly, or indirectly, fromadmixing of the specified ingredients in the specified amounts.

The present invention includes all possible stereoisomers and geometricisomers of compounds of structural formula (I). The present inventionincludes not only racemic compounds but also the optically activeisomers as well. When a compound of structural formula (I) is desired asa single enantiomer, it can be obtained either by resolution of thefinal product or by stereospecific synthesis from either isomericallypure starting material or use of a chiral auxiliary reagent, forexample, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883–888(1997). Resolution of the final product, an intermediate, or a startingmaterial can be achieved by any suitable method known in the art.Additionally, in situations where tautomers of the compounds ofstructural formula (I) are possible, the present invention is intendedto include all tautomeric forms of the compounds. As demonstratedhereafter, specific stereoisomers can exhibit an exceptional ability toinhibit HIV protease, and can be used alone or in combination with otherHIV and AIDS therapies.

As used herein, the term pharmaceutically acceptable salts referscompounds of structural formula (I) which contain acidic moieties andform salts with suitable cations. Suitable pharmaceutically acceptablecations include alkali metal (e.g., sodium or potassium) and alkalineearth metal (e.g., calcium or magnesium) cations. The pharmaceuticallyacceptable salts of the compounds of structural formula (I), whichcontain a basic center, are acid addition salts formed withpharmaceutically acceptable acids. Examples include the hydrochloride,hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,tartrate, gluconate, methanesulfonate, benzene sulfonate, andp-toluenesulfonate salts. In light of the foregoing, any reference tocompounds of the present invention appearing herein is intended toinclude compounds of structural formula (I), as well as pharmaceuticallyacceptable salts, prodrugs, and solvates thereof.

The term “prodrug” as used herein refers to compounds that are rapidlytransformed in vivo to a compound having structural formula (I), forexample, by hydrolysis. Prodrug design is discussed generally in Hardmaet al. (Eds.), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 9th ed., pp. 11–16 (1996). A thorough discussion isprovided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14,ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987). Typically, administration of a drug is followed by eliminationfrom the body or some biotransformation whereby the biological activityof the drug is reduced or eliminated. Alternatively, a biotransformationprocess can lead to a metabolic by-product, which is itself more orequally active compared to the drug initially administered. Increasedunderstanding of these biotransformation processes permits the design ofso-called “prodrugs,” which, following a biotransformation, become morephysiologically active in their altered state. Prodrugs, therefore,encompass compounds that are converted to pharmacologically activemetabolites.

To illustrate, prodrugs can be converted into a pharmacologically activeform through hydrolysis of, for example, an ester or amide linkage,thereby introducing or exposing a functional group on the resultantproduct. The prodrugs can be designed to react with an endogenouscompound to form a water-soluble conjugate that further enhances thepharmacological properties of the compound, for example, increasedcirculatory half-life. Alternatively, prodrugs can be designed toundergo covalent modification on a functional group with, for example,glucuronic acid, sulfate, glutathione, an amino acid, or acetate. Theresulting conjugate can be inactivated and excreted in the urine, orrendered more potent than the parent compound. High molecular weightconjugates also can be excreted into the bile, subjected to enzymaticcleavage, and released back into the circulation, thereby effectivelyincreasing the biological half-life of the originally administeredcompound.

The compounds of the present invention can be therapeuticallyadministered as the neat chemical, but it is preferable to administercompounds of structural formula (I) as a pharmaceutical composition orformulation. Accordingly, the present invention further provides forpharmaceutical formulations comprising a compound of structural formula(I), or pharmaceutically acceptable salts thereof, together with one ormore pharmaceutically acceptable carriers and, optionally, othertherapeutic and/or prophylactic ingredients. The carriers are“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

Inhibition of HIV protease typically is measured using a dose-responseassay in which a sensitive assay system is contacted with a compound ofinterest over a range of concentrations at which no or minimal effect isobserved, through higher concentrations at which partial effect isobserved, to saturating concentrations at which a maximum effect isobserved. Assays of the dose-response effect of inhibitor compounds canbe described as a curve expressing a degree of inhibition as a functionof concentration. The curve theoretically passes through a point atwhich the concentration is sufficient to reduce activity of the HIVprotease enzyme to a level that is 50% that of the difference betweenminimal and maximal enzyme activity in the assay. This concentration isdefined as the Inhibitory Concentration (50%) or IC₅₀.

Comparisons of the efficacy of inhibitors often are provided withreference to comparative IC₅₀ values, wherein a higher IC₅₀ valueindicates that the test compound is less potent, and a lower IC₅₀ valueindicates that the compound is more potent, than a reference compound.Compounds useful for the method of the present invention demonstrate anIC₅₀ value of less than 100 μM when measured using the dose-responseassay. Preferred compounds demonstrate an IC₅₀ value of less than 50 μM.More preferred compounds demonstrate an IC₅₀ value of less than 5 μM.Still more preferred compounds for the present invention demonstrate anIC₅₀ value of less than 3 μM (3000 nM), less than 0.5 μM (500 nM), andless than 0.1 μM (100 nM), for example, 5 pM to 0.1 nM.

Compounds and pharmaceutical compositions suitable for use in thepresent invention include those wherein the active ingredient isadministered in an effective amount to achieve its intended purpose.More specifically, a “therapeutically effective amount” means an amounteffective to inhibit development of, or to alleviate the existingsymptoms of, the subject being treated. Determination of the effectiveamount is well within the capability of those skilled in the art,especially in light of the detailed disclosure provided herein.

A “therapeutically effective dose” refers to that amount of the compoundthat results in achieving the desired effect. Toxicity and therapeuticefficacy of such compounds can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., fordetermining the LD₅₀ (the dose lethal to 50% of the population) and theED₅₀ (the dose therapeutically effective in 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, which is expressed as the ratio of LD₅₀ to ED₅₀. Compounds thatexhibit high therapeutic indices (i.e., a toxic dose that issubstantially higher than the effective dose) are preferred. The dataobtained can be used in formulating a dosage range for use in humans.The dosage of such compounds preferably lies within a range ofcirculating concentrations that include the ED50 with little or notoxicity. The dosage can vary within this range depending upon thedosage form employed, and the route of administration utilized.

The term “container” means any receptacle and closure therefore suitablefor storing, shipping, dispensing, and/or handling a pharmaceuticalproduct.

The term “insert” means information accompanying a product that providesa description of how to administer the product, along with the safetyand efficacy data required to allow the physician, pharmacist, andpatient to make an informed decision regarding use of the product. Thepackage insert generally is regarded as the “label” for a pharmaceuticalproduct.

The exact formulation, route of administration, and dosage can be chosenby the individual physician in view of the patient's condition. Dosageamount and interval can be adjusted individually to provide plasmalevels of the active moiety which are sufficient to maintain thetherapeutic effects.

Pharmaceutical compositions of the invention can be formulated toinclude a compound of structural formula (I) and one or more additionalagents useful in the treatment of HIV and AIDS. For example, compoundsof the present invention can be effectively administered at a period ofpreexposure and/or postexposure, in combination with a therapeuticallyeffective amount of an AIDS antiviral, immunomodulator, antiinfective,or vaccine, such as those disclosed in U.S. Pat. No. 6,245,806,incorporated herein by reference.

As appreciated by persons skilled in the art, reference herein totreatment extends to prophylaxis, as well as to treatment of establisheddiseases or symptoms. It is further appreciated that the amount of acompound of the invention required for use in treatment varies with thenature of the condition being treated, and with the age and thecondition of the patient, and is ultimately determined by the attendantphysician or veterinarian.

In general, however, doses employed for adult human treatment typicallyare in the range of 0.001 mg/kg to about 100 mg/kg per day. The desireddose can be administered in a single dose, or as multiple dosesadministered at appropriate intervals, for example as two, three, fouror more subdoses per day. In practice, the physician determines theactual dosing regimen which is most suitable for an individual patient,and the dosage varies with the age, weight, and response of theparticular patient. The above dosages are exemplary of the average case,but there can be individual instances in which higher or lower dosagesare merited, and such are within the scope of the present invention.

The terms “administration of” and “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to an individual in need of treatment.

Thus, in accordance with important features of the present invention, amethod of treating, and a pharmaceutical composition for treating, HIVinfection and AIDS are provided. The treatment involves administering toa patient in need of such treatment a pharmaceutical compositioncomprising a pharmaceutical carrier, a therapeutically effective amountof a compound of structural formula (I), and an optional agent useful inthe treatment of HIV or AIDS.

Compounds and compositions of the present invention can be administeredin a standard manner for the treatment of the indicated diseases, suchas orally, parenterally, transmucosally (e.g., sublingually or viabuccal administration), topically, transdermally, rectally, viainhalation (e.g., nasal or deep lung inhalation). Parenteraladministration includes, but is not limited to intravenous,intraarterial, intraperitoneal, subcutaneous, intramuscular,intrathecal, and intraarticular. Parenteral administration also can beaccomplished using a high pressure technique, like POWDERJECT™.

Such preparations also can be formulated as suppositories, e.g.,containing conventional suppository bases, such as cocoa butter or otherglycerides. Compositions for inhalation typically can be provided in theform of a solution, suspension, or emulsion that can be administered asa dry powder or in the form of an aerosol using a conventionalpropellant, such as dichlorodifluoromethane or trichlorofluoromethane.Typical topical and transdermal formulations comprise conventionalaqueous or nonaqueous vehicles, such as eye drops, creams, ointments,lotions, and pastes, or are in the form of a medicated plaster, patch,or membrane.

Additionally, compositions of the present invention can be formulatedfor parenteral administration by injection or continuous infusion.Formulations for injection can be in the form of suspensions, solutions,or emulsions in oily or aqueous vehicles, and can contain formulationagents, such as suspending, stabilizing, and/or dispersing agents.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle (e.g., sterile, pyrogen-free water)before use.

A composition of the present invention also can be formulated as a depotpreparation. Such long acting formulations can be administered byimplantation (for example, subcutaneously or intramuscularly) or byintramuscular injection. Accordingly, the compounds of the invention canbe formulated with suitable polymeric or hydrophobic materials (e.g., anemulsion in an acceptable oil), ion exchange resins, or as sparinglysoluble derivatives (e.g., a sparingly soluble salt).

For veterinary use, a compound of formula (I), or a nontoxic saltthereof, is administered as a suitably acceptable formulation inaccordance with normal veterinary practice. The veterinarian can readilydetermine the dosing regimen and route of administration that is mostappropriate for a particular animal.

As previously stated, the HIV protease inhibitors of the presentinvention can be administered as the sole active agent, or they can beused in combination with a second active agent which is effectiveagainst retroviruses, such as HIV-1. Such second active agents include,but are not limited to, other HIV protease inhibitors, variousnucleoside analogs, nonnucleoside reverse transcriptase inhibitors,antivirals, immunomodulators, antiinfectives, tat antagonists, andglycosidase inhibitors. Numerous examples of such second active agentsare set forth in U.S. Pat. Nos. 6,100,277 and 6,245,806, bothincorporated herein by reference, and include, but are not limited to,Ro 31-859, KNI-272, AZT, DDI, DDC, 3TC, D4T, PMEA, Ro 5-3335, Ro24-7429, indinavir, ritonavir, saquinavir, nelfinavir, amprenavir,abacavir, castanospremine, castanospermine 6-butryl ester,N-butyl-1-deoxy-nojirimycin, N-butyl-1-deoxynojirimycin per-butrylester, 097, acemannan, acyclovir, AD-439, AD-519, adefovir clipivoxil,AL-721, alpha interferon, ansamycin, beta-fluoro-ddA, BMS-232623,BMS-234475, CI-1012, cidofovir, delaviridine, EL-10, efaviren,famciclovir, FTC, hypericin, Compound Q, ISIS 2922, lobucavir,nevirapine, novapren, peptide T, octapeptide, PNU-140690, probacol,stavudine, valaciclovir, virazole, zalcitabine, ABT-378, bropirimine,gamma interferon, interleukin-2, TNF, etanercept, infliximab,fluconalzole, piritrexim, trimetrexate, daunorubicin, leukotriene B4receptor antagonist, and analogs and prodrugs thereof.

The protease inhibitors of the present invention and the second activeagent can be formulated as separate compositions which are administeredat substantially the same time, i.e., simultaneously or sequentially, orthe therapeutic agents can be administered from a single composition,such that all of the active agents are present in the host in atherapeutically effective amount. Alternatively, the therapeutic agentscan be administered to the host at different times, i.e., separately,such that only one or two active agents at a time are present in thehost in a therapeutically effective amount.

The compounds of structural formula (I) are effective antiviralcompounds and, in particular, are effective retroviral inhibitors. Thus,the subject compounds are effective HIV protease inhibitors. The subjectcompounds of the present invention also inhibit other retroviruses, suchas other lentiviruses, in particular, other strains of HIV, e.g., HIV-2,human T-cell leukemia virus, rous sarcoma virus, simian immunodeficiencyvirus, feline leukemia virus, feline immunodeficiency virus, and thelike. The compounds of structural formula (I), therefore, are effectivein the treatment and/or prophylaxis of retroviral infections.

In addition, the compounds of structural formula (I) are effective inpreventing the growth of retroviruses in a solution. Both human andanimal cell cultures, such as T-lymphocyte cultures, are utilized for avariety of purposes, such as research and diagnostic proceduresincluding calibrators and controls. Prior to and during the growth andstorage of a cell culture, the present inhibitors can be added to a cellculture medium at an effective concentration to prevent the unexpectedor undesired replication of a retrovirus that may inadvertently orunknowingly be present in the cell culture. For example, the virus maybe present originally in the cell culture because HIV is known to bepresent in human T-lymphocytes long before it is detectable in blood, orthrough exposure to the virus. This use of the present inhibitorsprevents the unknowing or inadvertent exposure of a potentially lethalretrovirus to a researcher or clinician.

The present invention, therefore, provides a pharmaceutical compositioncomprising a compound of structural formula (I), together with apharmaceutically acceptable diluent or carrier therefor. The presentinvention also provides a process of preparing a pharmaceuticalcomposition comprising mixing a compound of formula (I), together with apharmaceutically acceptable diluent or carrier therefor. Furtherprovided are articles of manufacture comprising a compound of structuralformula (I) and a second pharmaceutical drug, packaged separately ortogether, and an insert having instructions for using the active agents.

Specific, nonlimiting examples of compounds of structural formula (I)are provided below, the syntheses of which were performed in accordancewith the procedures set forth hereafter.

EXAMPLE 1

EXAMPLE 2

EXAMPLE 3

EXAMPLE 4

EXAMPLE 5

EXAMPLE 6

EXAMPLE 7

EXAMPLE 8

EXAMPLE 9

EXAMPLE 10

EXAMPLE 11

EXAMPLE 12

EXAMPLE 13

EXAMPLE 14

EXAMPLE 15

EXAMPLE 16

Generally, compounds of structural formula (I) can be prepared accordingto the synthetic schemes depicted herein. In these synthetic schemes, itis understood in the art that protecting groups can be employed wherenecessary in accordance with general principles of synthetic chemistry.These protecting groups are removed in the final steps of the synthesisunder basic, acidic, or hydrogenolytic conditions which are readilyapparent to those skilled in the art. By employing appropriatemanipulation and protection of chemical functionalities, synthesis ofcompounds of structural formula (I) not specifically set forth hereincan be accomplished by methods analogous to the scheme set forth herein.

Compounds of the present invention were tested for an ability to inhibitHIV-1 protease by the test method set forth below. The data set forthhereafter in the form of IC₅₀ values shows that compounds of the presentinvention are potent inhibitors of HIV protease.

HIV-1 Protease Inhibition Assay

The HIV-1 protease gene was subcloned into the pET30a vector (Novagen)and then transformed into BL21 (dE3)pLysS cells for protein expression.Protein expression and purification were followed according to Tang'sprocedure (Hong et al., Biochemistry, 1996, 35, 10627–10633).Accumulation of protein has resulted in cellular inclusion bodies. Thecell lysates analyzed by SDS-polyacrylamide gel electrophoresis showedthe expected 11 kDa major band. The inclusion body containing somebacterial proteins was thoroughly washed by using TRITON X-100,solubilized in 8M urea and passed through the Q-sepharose column toremove the bacterial proteins which interfered with subsequent refoldingsteps. HIV-1 protease was refolded from the urea to an active form bydialysis. As a final step, gel filtration chromatography was used toremove impurities after refolding. Activities of purified HIV-1 proteasewere examined using a fluorogenic substrate,2-aminobenzoyl-Thr-Ile-Nle-Phe(pNO2)-Gln-Arg-NH2 (Novabiochem). Kineticmeasurements of the cleavage of anthranilyl fluorogenic substrate byHIV-1 protease showed typical Michaelis-Menten behavior. The Michaelisconstant for the substrate is K_(m)=4.5 μM. Using the first rateequation, k_(cat) is calculated. In the condition of S_(o)<<K_(m),v=E_(o)(k_(cat)/K_(m))S_(o), where E_(o) is the total enzymeconcentration, and S_(o) is the substrate concentrate. Then,k_(cat)=0.70±0.05 s⁻¹. Assays are carried out as described by Toth andMarshall (Toth et al., Int. J. Pept. Protein Res., 1990, 36, 544–50).

EXPERIMENTALS (3aR,5R,6aR)-(Carbonic acid2′,5′-dioxo-pyrrolidin-1-yl-ester)-hexahydrocyclopenta[b]furan-5-yl-ester(4)

Key: (a) Thiourea, Rose Bengal, O₂, MeOH, hv, 8 h; (b) Ac₂O, Py, DMAP,CH₂Cl₂, 1 hour. 42% for two steps; (c) NaN₃, acetyl cholinesterase (typeV1-S) phosphonate buffer (0.5 M, pH 7.0), 12 hours, 70%; (d) TBSCl,imidazole, DMF, 30 min; (e) K₂CO₃, MeOH, 20 min. 94% for two steps; (f)NBS, ethyl vinyl ether, −45° C. to 23° C., 12 hours; (g) n-Bu₃SnH, AIBN,benzene, reflux, 4 hours; (h) BF₃.OEt₂, Et₃SiH, CH₂Cl₂, 0° C., 10 min.;(i) 45% aq. HF, CH₃CN, 15 min.; (j) DSC, Et₃N, CH₃CN, 2 hours, 47% fortwo steps.

A cold solution of cyclopentadiene (16 mL), thiourea (10 g), and RoseBengal (300 mg) in methanol (MeOH) (1000 mL) was purged with oxygen andirradiated with a 75 Watt halogen lamp. After 8 hours, the solution washeld at room temperature in the absence of light for 12 hours. Solventswere evaporated under reduced pressure, then MeOH (200 mL) was added.After filtering, the filtrate was concentrated and the crude product waspassed through a silica gel column to provide a crude diol.

The crude diol, acetic anhydride (Ac₂O) (58.8 g, 0.57 moles), pyridine(77 g, 1.15 moles), and DMAP (4-dimethylaminopyridine) (200 mg) inmethylene chloride (CH₂Cl₂) (1000 mL) were stirred for 2 hours. Thereaction mixture was washed with water (2×300 mL) then concentrated. Theresulting crude diacetate was purified by silica gel chromatography toobtain 17.9 g (42%, two steps) of the diacetate. ¹H NMR (CDCl₃, 200MHz): δ 6.07 (m, 2H), 5.5 (m, 2H), 2.85 (m, 1H), 2.05 (s, 6H), 1.7 (m,1H).

The diacetate (4.1 g, 22.8 mmol), sodium azide (NaN₃) (15 mg), andacetyl cholinesterase (2.8 mg, type VI-S; from Electric Eel, Sigma,Inc.) were slowly stirred in phosphate buffer (0.5 M, pH 7.0) for 12hours. Then, the reaction mixture was extracted with EtOAc (EtOAc)(3×200 mL), washed with brine (200 mL), and concentrated under reducedpressure. The crude product was purified by silica gel chromatography toobtain 2.2 g (70%) of compound 1; [α]²⁵ _(D): +59.35 (89% ee).

(1R,4S)-4-(tert-Butyl-dimethylsilanyloxy)-cyclopent-2-enol (2)

The alcohol (200 mg, 1.48 mmol), tert-butyldimethylsilanyl chloride(TBSCl) (267 mg, 1.48 mmol), and imidazole (191 mg, 2.86 mmol) indimethylformamide (DMF) (10 mL) were stirred for 30 minutes. Then, thereaction mixture was diluted with EtOAc (50 mL) and washed several timeswith water (2×50 mL). The organic layer was dried over anhydrous sodiumsulfate (Na₂SO₄) and the solvents were evaporated in vacuo. Purificationof the crude product by silica gel chromatography provided the TBS etheras a colorless liquid. The TBS ether and potassium carbonate (K₂CO₃)(323 mg, 2.34 mmol) in MeOH (10 mL) were stirred for 20 minutes at roomtemperature. The MeOH was evaporated and the reaction mixture wasextracted with EtOAc (2×50 mL), dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. Silica gel chromatographicpurification of the crude product provided compound 2 (300 mg, 94%, twosteps) as a colorless oil. ¹H NMR (CDCl₃, 200 MHz): δ 5.92 (m, 2H), 4.6(m, 2H), 2.68 (m, 1H), 1.77 (m, 1H), 1.49 (m, 1H), 0.90 (s, 9H), 0.09(s, 6H).

(3aR,5R,6aR)-5-tert-Butyldimethysiloxy-hexahydrocyclopenta[b]furan (3)

A solution of compound 2 (300 mg, 1.4 mmol) and N-bromosuccinimide (NBS)(248 mg, 1.4 mmol) in CH₂Cl₂ (5 mL) at −45° C. was added to ethyl vinylether (151 mg, 2.1 mmol). The resulting mixture was warmed to roomtemperature and, after 12 hours, treated with aq. ammonium chloride(NH₄Cl) (10 mL), then washed with brine (50 mL). The organic layer wasdried over anhydrous Na₂SO₄, then concentrated in vacuo. Purification ofthe crude product by silica gel chromatography provided a bromoethoxycompound (468 mg) as colorless liquid.

The bromoethoxy compound (464 mg, 1.18 mmol), tri-n-butyltin hydride(nBu₃SnH) (412 mg, 1.41 mmol), and AIBN (10 mg) in benzene (5 mL) wererefluxed for 4 hours. The reaction mixture then was cooled to roomtemperature, and the crude product was chromatographed on silica gel toobtain a bicyclic ether (300 mg) as a viscous liquid.

To the bicyclic ether and triethylsilane (Et₃SiH) (331 mg, 2.85 mmol) inCH₂Cl₂ (5 mL) at 0° C. was added boron trifluoride etherate (BF₃.OEt₂)(2.85 mmol). The reaction was complete in 10 minutes. Sodium bicarbonate(NaHCO₃) (10 mL) was added and the reaction mixture was extracted withCH₂Cl₂ (2×10 mL). The combined extracts were dried over anhydrous Na₂SO₄and concentrated in vacuo. Purification by silica gel chromatographyprovided compound 3 as a colorless liquid. ¹H NMR (CDCl₃, 400 MHz): δ4.39 (m, 1H), 4.06 (m, 1H), 3.88 (m, 1H), 3.78 (m, 1H), 2.53 (m, 1H),2.1–1.9 (m, 3H),1.72 (m, 1H),1.58 (m, 1H),1.42 (m, 1H),0.91 (s, 9H),0.03 (s, 6H).

(3aR,5R,6aR)-(Carbonicacid-2′,5′-dioxo-pyrrolidin-1-ylester)-hexahydro-cyclopenta[b]furan-5-ylester (4)

Ether 3 (175 mg, 0.72 mmol), HF (45%, 0.2 mL), and CH₃CN (2 mL) werestirred in a plastic container for 15 minutes. Aq. NaHCO₃ (5 mL) wasadded to the mixture and the contents of the flask were extracted withEtOAc. The combined organic layer was washed with brine (10 mL) toobtain the crude alcohol which was purified by silica gelchromatography. [α]²⁵ _(D): −14.67°, c, 1.85, CHCl₃. ¹H NMR (CDCl₃, 200MHz): δ 4.36 (dt, 1H, J=1.43 Hz, 6.4 Hz), 4.22 (m, 1H), 3.98 (m, 1H),3.58 (m, 1H), 2.71 (m, 1H), 2.5 (s, 1H), 2.2–1.5 (m, 6H).

The above alcohol (73 mg, 609 mmol), N,N′-disuccinimidyl carbonate (187mg, 0.731 mmol), and triethylamine (Et₃N) (92 mg, 0.913 mmol) in CH₃CN(2 mL) were stirred for 12 hours. The solvents were evaporated and thecrude alcohol was purified by silica gel chromatography to providecarbonate 4 (91 mg, 47%, two steps).

(3aS,5S,6aS)-(Carbonic acid 2′,5′-dioxo-pyrrolidin-1-ylester)-hexahydrocyclopenta[b]furan-5-yl ester (6)

Key: (a) NBS, ethyl vinyl ether, −45° C. to 23° C., 12 hours; (b)n-Bu₃SnH, AIBN, benzene, reflux, 4 hours; (c) BF₃ OEt₂, Et₃SiH, CH₂Cl₂,0° C., 10 min., 58% for three steps; (d) K₂CO₃, MeOH, 90 min; and (j)DSC, Et₃N, CH₃CN, 12 hours, 92% for two steps.

(3aS,5S,6aS)-Acetic acid hexahydrocyclopenta[b]-furan-5-yl ester (5)

To alcohol 1 (199 mg, 1.4 mmol) and N-bromosuccinimide (249 mg, 1.4mmol) in CH₂Cl₂ (5 mL) at −45° C. was added ethyl vinyl ether (152 mg,2.11 mmol) using the same reaction conditions as in the synthesis ofcompound 3 to obtain a bromo compound (332 mg). ¹H NMR (CDCl₃, 200 MHz):δ 6.0 (m, 2H), 5.5 (m, 1H), 4.7 (m, 2H), 3.6 (m, 2H), 3.35 (d, 2H, J=5.3Hz), 2.8 (m, 1H), 2.0 (s, 3H), 1.8 (m, 1H), 1.2 (t, 3H, J=7 Hz).

The bromo compound (332 mg, 1.13 mmol), nBu₃SnH (395 mg, 1.35 mmol), and2,2′-azobisisobutyronitrile (AIBN) (20 mg) in toluene were refluxed asdescribed in the synthesis of compound 3 to obtain a bicyclic ether (228mg) as a colorless oil.

To the bicyclic ether (228 mg, 1.065 mmol) and Et₃SiH (370 mg, 3.196mmol) in CH₂Cl₂ (5 mL) at room temperature, was added BF₃.OEt₂ (450 mg,3.196 mmol) following the same reaction conditions as described in thesynthesis of compound 3 to obtain compound 5 (140 mg, 58% three steps)as an oil. ¹H NMR (CDCl₃, 200 MHz): δ 5 (m, 1H), 4.5 (m, 1H), 3.95 (m,1H), 3.74 (m, 1H), 2.7 (m, 1H), 2.1 (m, 3H), 2 (s, 3H), 1.5–1.9 (m, 3H).

(3aS,5S,6aS)-(Carbonic acid 2′,5′-dioxo-pyrrolidin-1-ylester)-hexahydrocyclopenta[b]furan-5-yl ester (6)

Compound 5 (133 mg, 0.78 mmol) and K₂CO₃ (215 mg, 1.56 mmol) in MeOH (5mL) were stirred for 1.5 hours. The reaction mixture then was dilutedwith EtOAc (20 mL) and washed several times with water. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure at 30° C. to obtain a volatile alcohol. [α]²⁵ _(D): +8.6, c,0.7, CHCl₃.

The alcohol, N,N′-disuccinimidyl carbonate (240 mg, 0.938 mmol), andEt₃N (157 mg, 1.56 mmol) in acetonitrile (5 mL) were stirred for 12hours. Then, the reaction mixture was diluted with EtOAc (20 mL), andwashed with brine (20 mL). The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude product waspurified by a silica gel column to obtain compound 6 (195 mg, 92%, twosteps) as an oil. ¹H NMR (CDCl₃, 300 MHz): δ 5.1 (m, 1H), 4.48 (m, 1H),3.95 (m, 1H), 2.0–2.3 (m, 4H), 1.8 (m, 2H).

Synthesis of 4-hydroxy-3-methylbenzoic acid (8)

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl esterhexahydro-furo[2,3-b]furan-3-yl ester (15) and (16)

Key: (a) N-iodosuccinimide, propargyl alcohol, CH₂Cl₂, 0–23° C., 2hours, 92%; (b) Cobaloxime (cat), NaBH₄, EtOH, 50° C., 2 hours, 73% orBu₃SnH, AIBN, toluene, reflux, 1 hour, 76%; (c) O₃, CH₂Cl₂ MeOH, 30 min,Me₂S, −78 0° C. to 23° C., 30 min; (d) NaBH₄, EtOH, 0° C., 2 hours, 75%;(e) immobilized lipase 30, Ac₂O, DME, 23° C. 42%; (f) DSC, Et₃N, CH₃CN,24 hours, 75%; (g) K₂CO₃, MeOH, 1 h; (h) DSC, Et₃N, CH₃CN, 1 hour, 73%for two steps.

Trans-2-(propargyloxy)-3-iodotetrahydrofuran (10)

To a stirred, ice cold suspension of 15 g (66.6 mmol) ofN-iodosuccinimide in 150 mL of CH₂Cl₂ was added a mixture ofdihydrofuran (66.6 mmol, 4.67 g, 5.1 mL) and propargyl alcohol (100mmol, 5.0 g, 5.2 mL) in 50 mL of CH₂Cl₂ over 20 min. After warming to24° C. with stirring over 2 hours, 200 mL of water was added and thestirring was continued for 1 hour. The layers were separated and theaqueous layer extracted with 2×100 mL of CH₂Cl₂. The combined organicextracts were washed with a brine solution containing a small amount ofsodium thiosulfate (Na₂S₂O₃) (70 mg), dried over anhydrous Na₂SO₄,filtered, and concentrated. Chromatography over silica gel using 30%EtOAc in hexane yielded (15.4 g, 92%) of iodoether 10 as an oil. ¹H-NMR(CDCl₃): δ 5.4 (br s, 1H), 4.0–4.3 (m, 5H), 2.7 (m, 1H), 2.48 (br s,1H), 2.25 (m, 1H); IR (neat), 2956, 2180, 1621, 1440 cm⁻¹.

(3aR,6aS) and (3aS,6aR)-3-methylene-4H-hexahydro-furo[2,3-b]furan (11)(Tributyltin Hydride Procedure)

To a refluxing solution of tributyltin hydride (20.7 mL, 77 mmol)containing AIBN (100 mg) in toluene (200 mL) was added a solution of15.4 g (61 mmol) of iodotetrahydrofuran 10 in toluene (50 mL) dropwiseover a one-hour period. The resulting mixture was stirred at reflux foran additional 4 hours (monitored by TLC). The mixture then was cooled to23° C. and concentrated under reduced pressure. The residue waspartitioned between petroleum ether and acetonitrile (200 mL of each),and the acetonitrile (lower) layer was concentrated. The residue waspurified by chromatography on silica gel, using 10% EtOAc in hexane asthe eluent to provide the product 11 (5.84 g, 76%) as an oil. ¹H-NMR(CDCl₃): δ 5.7 (d, 1H, J=4.9 Hz), 4.9–5.1 (m, 2H), 4.3–4.6 (m, 2H),3.7–4.0 (m, 2H), 3.3 (m, 1H), 1.8–2.2 (m, 2H); IR (neat), 2970, 1645,1430 cm⁻¹.

(3aR,6aS) and (3aS,6aR)-3-methylene-4H-hexahydro-furo[2,3-b]furan (11)(Catalytic Cobaloxime Procedure)

To a solution of iodoether 10 (6.4 g, 25.4 mmol) in 95% ethanol (80 mL)was added solid sodium borohydride (NaBH₄) (1.06 g, 28 mmol) and 10 Nsodium hydroxide (NaOH) (2.6 ml, 26 mmol). The solution was flushed withN₂ and several portions of finely powered cobaloxime (611 mg, 1.5 mmol)were added over a one-hour period at 50° C. (bath temperature 65° C.).The resulting mixture was stirred for an additional hour, then thereaction mixture was concentrated under reduced pressure. The resultingresidue was diluted with brine and the mixture was thoroughly extractedwith ether (3×150 mL). The combined organic layers were washed withwater, then brine, and dried over anhydrous Na₂SO₄. Evaporation of thesolvent gave a residue which was chromatographed over silica gel toprovide the product 11 (2.3 g, 73%) as an oil. ¹H-NMR (CDCl₃): δ 5.7 (d,1H, J=4.9 Hz), 4.9–5.1 (m, 2H), 4.3–4.6 (m, 2H), 3.7–4.0 (m, 2H), 3.3(m, 1H), 1.8–2.2 (m, 2H); IR (neat): 2970, 1645, 1430 cm⁻¹; MS (70 eV)m/z 126 (m+).

(3S,3aR,6aS) and (3R,3aS,6aR)-3-hydroxy-4H-hexahydrofuro[2,3-b]furan(12)

A stream of ozone was dispersed into a solution of compound 11 (5.84 g,46.4 mmol) in MeOH (150 mL) and CH₂Cl₂ (150 mL) at −78° C. for 30 min.The resulting blue solution was purged with nitrogen until colorless,then quenched with 20 mL of dimethyl sulfide. The resulting mixture wasallowed to warm to 23° C. The mixture then was concentrated underreduced pressure to afford a crude ketone. The ketone was dissolved inethanol (50 mL), cooled to 0° C., and sodium borohydride (2.1 g, 55.6mmol) was added. The reaction mixture was stirred for an additional 2hours at 0° C., and then quenched with 10% aqueous citric acid (10 mL).The resulting mixture was concentrated under reduced pressure, and theresidue was partitioned between EtOAc and brine. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×100 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated carefully under reduced pressure. The resulting residue waschromatographed over silica gel using 30% EtOAc in hexane as the eluentto furnish (4.52 g, 75%) the racemic alcohol 12 as an oil. ¹H-NMR(CDCl₃): δ 5.7 (d, J=5.13, 1H), 4.45 (dd, J=6.8, 14.6, 1H), 3.9–4.0 (m,3H), 3.65 (dd, 1H, J=7, 9.1), 2.9 (m, 1H), 2.3 (m, 1H), 1.85 (m, 2H); IR(neat): 2951, 1640, 1346, 1210 cm⁻¹; MS (70 eV) m/z 131 (m++ H).

Preparation of Immobilized Amano Lipase 30

Commercially available celite 521 (4 g, Aldrich) was loaded on a Buchnerfunnel and washed successively with 50 mL of deionized water and 50 mLof 0.05 N phosphate buffer (pH═7.0; Fisher Scientific). The washedcelite then was added to a suspension of 1 g of Amano lipase 30 in 20 mLof 0.05 N phosphate buffer. The resulting slurry was spread on a glassdish and allowed to air dry at 23° C. for 48 hours (weight 5.4 g; watercontent about 2% by Fisher method).

(3R,3aS,6aR)-3-hydroxyhexahydrofuro[2,3-b]furan (13) by ImmobilizedLipase Catalyzed Acylation

To a stirred solution of racemic alcohol 12 (2 g, 15.4 mmol) and Ac₂O (4g, 42.4 mmol) in 100 mL of DME (ethylene glycol dimethyl ether) wasadded 2.7 g (about 25% by weight of lipase, PS30) of immobilized Amanolipase and the resulting suspension was stirred at 23° C. The reactionwas monitored by TLC and ¹H NMR analysis until 50% conversion wasattained. The reaction mixture was filtered, and the filter cake waswashed repeatedly with EtOAc. The combined filtrate was carefullyconcentrated in a rotary evaporator, maintaining the bath temperaturebelow 15° C. The residue was chromatographed over silica gel to provide843 mg (42%) of compound 13 (95% ee; [α]²⁵ _(D): −11.9°, c 1.24, MeOH);¹H-NMR (CDCl₃): δ 5.7 (d, 1H, J=5.1 Hz), 4.45 (dd, 1H, J=6.8, 14.6 Hz),3.85–4.0 (m, 3H), 3.65 (dd, 1H, J=7.0, 9.1 Hz), 2.9 (m, 1H), 2.3 (m,1H), 1.85 (m, 2H); also, 1.21 g of compound 14 after washing with 5%aqueous sodium carbonate (45%, [α]²⁵ _(D): +31.8°, c 1.86, MeOH); 1H-NMR(CDCl₃): δ 5.7 (d, 1 H, J=5.2 Hz), 5.2 (dd, 1H, J=6.4, 14.5 Hz), 3.8–4.1(m, 3H), 3.75 (dd, 1H, J=6.6, 9.2 Hz), 3.1 (m, 1H), 2.1 (s, 3H),1.85–2.1 (m, 2H); IR (neat): 2947, 1750, 1630, 1338, 1220 cm⁻¹.

(3S,3aS,6aR)-Carbonic acid 2,5-dioxo-pyrrolidin-1-yl esterhexahydrofuro[2,3-b]furan-3-yl ester (15)

Compound 13 (2 g, 15.3 mmol), N,N′-disuccinimidyl carbonate (4.76 g,18.5 mmol), and triethylamine (Et₃N) (4.12 g, 40.8 mmol) in acetonitrile(CH₃CN) (50 mL) were stirred for 24 hours. The reaction mixture then wasdiluted with EtOAc (100 ml), washed several times with brine, then driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to providecrude compound 15, which was purified by column chromatography to obtainthe active carbonate 15. Yield (3.1 g, 75%), m.p 128–130° C. ¹H NMR(CDCl₃, 200 MHz): δ 5.74 (d, 1H, J=5.1 Hz), 5.26 (m, 1H), 4 (m, 4H), 3.1(m, 1H), 2.84 (s, 4H), 1.88–2.2 (m, 2H).

(3S,3aS,6aR)-Carbonic acid 2,5-dioxo-pyrrolidin-1-yl esterhexahydrofuro[2,3-b]furan-3-yl ester (16)

Compound 14 (500 mg, 2.9 mmol) and K₂CO₃ (802 mg, 5.8 mmol) in MeOH (25mL) were stirred for 1 hour. The reaction mixture then was diluted withEtOAc (60 mL) and washed several times with brine (50 mL). The aqueouslayer was extracted with EtOAc (40 mL), and the combined extracts weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by a silica gel column to obtain a bicyclicalcohol.

The bicyclic alcohol, N,N′-disuccinimidyl carbonate (890 mg, 3.48 mmol),and Et₃N (585 mg, 5.8 mmol) were subjected to same conditions as in thepreparation of compound 15 to provide compound 16 (573 mg, 73%, twosteps). [α]²⁵ _(D): +22.5°, c, 1.6, MeOH. ¹H NMR (CDCl₃, 200 MHz): δ5.76 (d, 1H, J=5.2 Hz) 5.25 (m, 1H), 3.9–4.3 (m, 4H), 3.14 (m, 1H), 2.85(s, 4H), 1.9–2.2 (m, 2H).

Synthesis of Pyridyl Mixed Carbonates (18) and (20)

Key: (a) NaBH₄, MeOH, 0° C., 15 min.; (b) DSC, Et₃N, CH₃CN, 1 hour, 90%for two steps.

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester pyridin-3-yl methyl ester(18)

To compound 17 (430 mg, 4 mmol) in MeOH (10 mL) at 0° C. was added NaBH₄(279 mg, 8 mmol) in one portion. After 15 min., the reaction mixture wasdiluted with EtOAc (20 mL) and washed with brine (20 mL). The organiclayer was dried over anhydrous Na₂SO₄, then concentrated under reducedpressure to obtain an alcohol, which was filtered through silica gelcolumn, then concentrated.

The above alcohol, N,N′-disuccinimidyl carbonate (1.47 g, 5.76 mmol),and Et₃N (606 mg, 6 mmol) in CH₃CN (10 mL) were stirred for 1 hour. Thereaction mixture then was diluted with EtOAc (20 mL) and washed severaltimes with water, and dried over anhydrous Na₂SO₄. The crude product waspurified by silica gel column to obtain compound 18 (900 mg, 90%, twosteps). This carbonate was unstable and was used immediately.

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester pyridin-4-yl methyl ester(20)

To compound 19 (400 mg, 3.7 mmol) in MeOH (10 mL) at 0° C. was addedNaBH₄ (236 mg, 7.4 mmol) in one portion following the conditions used inthe preparation of compound 18 to obtain an alcohol that was filteredthrough a silica gel column, then concentrated.

The alcohol, N,N′-disuccinimidyl carbonate (1.4 g, 5.5 mmol), and Et₃N(606 mg, 6 mmol) in CH₃CN (10 mL) were allowed to react under the sameconditions used in the preparation of compound 18 to obtain compound 20(824 mg, 88%, two steps). This carbonate also was unstable and was usedimmediately.

(3S)-Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester tetrahydrofuran-3-ylester (22)

Key: (b) DSC, Et₃N, CH₃CN, 12 hours, 92%

Compound 21 (250 mg, 2.84 mmol), N,N′-disuccinimidyl carbonate (799 mg,3.12 mmol), and Et₃N (431 mg, 4.27 mmol) in CH₃CN (5 mL) were stirredfor 12 hours at room temperature. Then the reaction mixture was dilutedwith EtOAc (20 mL), washed with brine, then concentrated under reducedpressure to obtain compound 22 (595 mg, 92%) as a solid. M.P.: 97–99° C.

1-(3-Hydroxypropyl)-2-(tetrahydropyran-2-yloxy)-cyclopentanol (25)

Key: (a) DHP, CH₂Cl₂, 1.5 hours 63%; (b) allyl magnesium bromide, THF,0° C., 73%; (c) 9-BBN, THF, 12 hours, then MeOH, H₂O₂, NaOH, 650° C., 1h 68%; (d) MsCl, Py, 12 hours; (e) TsOH, MeOH, 30 min. 60%; (f) DSC,Et₃N, CH₃CN, 12 hours, 40%.

Compound 24 (1.13 g, 13 mmol) and dihydropyran (DHP) (1.42 g, 16.9 mmol)in CH₂Cl₂ (25 mL) were stirred for 1.5 hours. Aq. NaHCO₃ (10 mL) wasadded, and the reaction mixture was extracted with CH₂Cl₂ (10 mL). Thecombined extracts were dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. Purification of the crude product by silica gelcolumn provided the THP-protected hydroxyketone (540 mg, 63%) as an oil.¹H NMR (CDCl₃, 200 MHz): δ 5.9 (m, 1H), 5.1 (m, 2H), 4.7 (m, 1H), 3.9(m, 2H), 3.5 (m, 1H), 2.1–2.5 (m, 2H), 1.3–2.0 (m, 12H).

The ketone (500 mg, 2.7 mmol) in THF (10 mL) was cooled to 0° C., andallyl magnesium bromide (5.4 mL, 5.4 mmol) was added dropwise. After 3hours at room temperature, the reaction mixture was treated with aq.NH₄Cl (10 mL), then diluted with EtOAc (20 mL). The organic layer waswashed with brine and dried over anhydrous Na₂SO₄. Solvents wereevaporated under reduced pressure and the crude product was purified bysilica gel column to obtain mixture of diastereomers (443 mg, 73%) as anoil.

The mixture (260 mg, 1.15 mmol) and 9-BBN (9-borabicyclo[3.3.1]nonane)(9.2 mL, 4.6 mmol, 0.5M solution) in THF at 0° C. were stirred for 12hours at room temperature. MeOH (0.3 mL), hydrogen peroxide (H₂O₂) (2.5mL, 30%), NaOH (7 mL, 30%) were heated at 65° C. for 1 hour. Aftercooling to room temperature, the solvents were evaporated under reducedpressure and the crude product was purified by silica gel column toobtain compound 25 (191 mg, 68%) as an oil. ¹H NMR (CDCl₃, 400 MHz): δ4.7 (m, 1H), 3.8, 3.7, and 3.5 (three m, 5H), 2.5 (br s, 2H), 1.4–2 (m,16H).

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 1-oxa-spiro[4.4]non-6-ylester (26)

To the diol 25 (170 mg, 0.69 mmol) and pyridine (1 mL) was addedmethanesulfonyl chloride (MsCl) (103 mg, 0.9 mmol). The resultingmixture was stirred for 12 hours. Then the mixture was diluted withEtOAc (10 mL) and the organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecyclic ether was purified by silica gel column to obtain (111 mg, 71%)of the cyclic product. ¹H NMR (CDCl₃, 400 MHz): 5.71 (m, 1H), 3.95 (m,4H), 3.87 (m, 1H), 1.6–2 (m, 16H).

To the above ether (110 mg, 0.48 mmol) in MeOH (5 mL) was addedp-toluenesulfonic acid (TsOH) (16 mg). After stirring for 30 min, thesolvent was evaporated and the crude product was extracted with EtOAc(2×10 mL) and the organic layers were washed with brine (10 mL) andconcentrated. Purification by silica gel column provided the spiroalcohol (41 mg, 60%) as an oil. ¹H NMR (CDCl₃, 400 MHz): δ 4.1 (m, 1H),3.7 (m, 2H), 1.5–2 (m, 10H).

The above spiro alcohol (27 mg, 0.19 mmol), N,N′-disuccinimidylcarbonate (52 mg, 0.204 mmol), Et₃N (25 mg, 0.25 mmol) in CH₃CN (5 mL)were stirred for 12 hours, following the same conditions as describedfor compound 22 to obtain compound 26 (22 mg, 40%). ¹H NMR (CDCl₃, 200MHz): δ 4.7 (m, 1H), 3.8 (m, 2H), 2.8 (s, 4H), 1.5–2.1 (m, 10H).

(2S)-Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester2-oxo-thiazolidin-4-ylmethyl ester (29)

Key: (a) (COCl)₂, KOH, water, 2 hours; (b) EtOH, conc. HCl, 12 hours,20%, two steps (c) NaBH₄, MeOH 3 hours (a) DSC, Et₃N, CH₃CN, 12 hours.

To compound 27 (2.42 g, 20 mmol) and potassium hydroxide (KOH) (40%, 5mL) in water (30 mL), at 0° C., was added oxalyl chloride ((COCl)₂) (13mL, 20%). After stirring for 2 hours, the biphasic layer was placed inseparating funnel. The organic layer was discarded and the aqueous layerwas washed with ether (10 mL), then acidified to pH 1 with 10% HCl (20mL). The water then was evaporated under reduced pressure. The solidresidue was extracted with hot ethanol (EtOH) (4×25 mL). The EtOH layerwas concentrated to 20 mL and 0.2 mL of conc. HCl was added, followed bystirring for 12 hours. Ethanol then was evaporated and the crude productwas extracted with EtOAc (2×25 mL). Concentration and purification bysilica gel column provided the ethyl ester (668 mg, 20%, two steps) asan oil.

The ethyl ester was subjected to NaBH₄ (2–3 equiv.) reduction in MeOHfor 2–3 hours at room temperature to obtain alcohol 28. Treatment ofalcohol 28 with N,N-disuccinimidyl carbonate (2 equiv.) and Et₃N (4equiv) in CH₃CN for 12–24 hours provided the mixed carbonate 29 inexcellent yield.

Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester quinolin-4-ylmethyl ester(31)

Key. (a) NaBH₄, MeOH, 0° C., 12 hours quantitative; (b) DSC, Et₃N,CH₃CN, 1 hour, 58% for two steps.

To compound 30 (300 mg, 2 mmol) in MeOH (5 mL) at 0° C. was added NaBH₄(145 mg, 3.8 mmol). The resulting mixture was stirred for 12 hours.Standard workup and purification afforded the corresponding alcohol inquantitative yield.

The alcohol (50 mg, 0.31 mmol), N,N′-disuccinimidyl carbonate (1128 mg,0.5 mmol), and Et₃N (63 mg, 0.63 mmol) in CH₃CN (2 mL) were stirred for12 hours. After dilution with EtOAc (10 mL) and washing several timeswith brine (3×10 mL), the organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain compound 31 (52 mg, 58%) assolid. M.P.: 94° C. ¹H NMR (CDCl₃, 400 MHz): δ 8.9 (d, 1H, J=4.4 Hz),8.1 (d, 1H, J=8.5 Hz), 7.9 (d, 1H, J=8.3 Hz), 7.74 (m, 1H) 7.63 (m, 1H),7.49 (d, 1H, J=4.3 Hz), 2.84 (s, 4H).

3-(Tetrahydropyran-2-yloxy)benzenesulfonyl chloride (33)

Key: (a) NaNO₂, H₂SO₄, H₂O, 0° C., 30 min.; (b) SOCl₂, DMF, reflux, 4hours; (c) DHP, PPTS, CH₂Cl₂, 1 hour.

To a solution of compound 32 (5 g, 29 mmol) and sulfuric acid (H₂SO₄)(8.6 g, 88 mmol) in water (100 mL) at 0° C. was added sodium nitrite(NaNO₂) (2.2 g, 32 mmol) in portions. Then the reaction mixture wasstirred for 30 minutes at room temperature, followed by boiling for 20minutes. The red solution was concentrated under reduced pressure. Theresulting crude product was extracted with hot EtOH (2×100 mL). Allextractions were concentrated and treated with aq. NaOH solution untilbasic, and again concentrated to provided the sodium salt of the crude3-hydroxybenzenesulfonic acid.

The salt (5.6 g, 29 mmol) and thionyl chloride (SOCl₂) (15 mL) wererefluxed, and dimethylformamide (DMF) (0.1 mL) was added. Refluxing wascontinued for 4 hours. The reaction mixture then was cooled to roomtemperature, diluted with EtOAc (100 mL), and the organic layer washedwith brine (2×50 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. Purification ofthe resulting crude product by flash silica gel chromatography providedthe hydroxybenzenesulfonyl chloride.

To the sulfonyl chloride (1 g, 5.2 mmol) and DHP (0.87 g, 10 mmol) inCH₂Cl₂ (25 mL) was added PPTS (pyridinium p-toluenesulfonate) (100 mg).The reaction mixture was stirred for 1 hour at room temperature. Thenthe reaction mixture was diluted with CH₂Cl₂ (20 mL) and the organiclayer washed with aq. NaHCO₃ solution (20 mL) and brine (2×20 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄ and evaporatedunder reduced pressure. Purification of the resulting crude product byflash silica gel chromatography provided compound 33 (670 mg, 56%). ¹HNMR (CDCl₃, 200 MHz): δ 7.67 (m, 1H), 7.55 (m, 1H), 7.4 (m, 1H), 5.5 (m,1H), 3.9 and 3.6 (two m, 2H), 1.5–2 (m, 6H).

Bisacetoxy Toluenesulfonyl Chlorides (35), (37), and (37b)

Key: (a) H₂SO₄, Ac₂O, AcOH, CrO₃, 0° C.-5° C., 33%.

Acetic acid acetoxy-(4-chlorosulfonylphenyl)methyl ester (35)

To compound 34 (2 g, 10.5 mmol), H₂SO₄ (2 g, 21 mmol), Ac₂O (8 mL), AcOH(8 mL) at 0° C.-5° C. was added CrO₃ (2.1 g, 21 mmol) in portions. Theresulting reaction mixture was monitored by TLC. When the reaction was50% complete, ice cold water (50 mL) was added, and the reaction mixtureextracted with EtOAc. The organic layer was washed with brine (2×20 mL)and then aq. NaHCO₃ solution. The combined organic layer was dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. Purification ofthe resulting crude product by flash silica gel chromatography providedcompound 35 (1.09 g, 33%). ¹H NMR (CDCl₃, 200 MHz): δ 8.0 (d, 2H, J=6.7Hz), 7.78 (m, 3H), 2.15 (s, 6H).

Acetic acid acetoxy-(3-chlorosulfonylphenyl)methyl ester (37)

The same procedure was followed as for the preparation of compound 35starting with m-toluenesulfonyl chloride (36). ¹H NMR (CDCl₃, 200 MHz):δ 8.19 (m, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.65 (m, 1H), 2.16 (s, 6H)

Acetic acid acetoxy-(3-chlorosulfonyl-2-methyl-phenyl)methyl ester (37b)

Following the same reaction under controlled conditions as described forcompound 35, a mixture of isomers of compound 37b was obtained.

3,5-Bis-(tetrahydropyran-2-yloxy)benzenesulfonyl chloride (39)

Key: (a) SO₂, NaHCO₃, 6 hours then compound 38, reflux, four days; (b)SO₂Cl, reflux, DMF, 50% for two steps; (c) DHP, PPTS, CH₂Cl₂, 1 hour,67%.

To a suspension of NaHCO₃ (10 g, 119 mmol) in water (30 mL) was bubbledSO₂ gas. Bubbling continued until the NaHCO₃ was solubilized (6 hours).To this yellow solution (exit gases have a pH 1–2) was addedphloroglucinol 38 (5 g, 30.8 mmol). The reaction mixture was refluxedfor four days, then cooled to room temperature, the solvent evaporated,and the resulting solid was dried to obtain 3,5-dihydroxybenzenesulfonicacid.

The crude acid (500 mg, 2.35 mmol) and SO₂Cl (7 mL) were refluxed in thepresence of DMF (0.1 mL) for 40 minutes. The resulting reaction mixturewas extracted with EtOAc (50 mL) and the organic layer washed with brine(2×20 mL) and aq. NaHCO₃ solution. The combined organic layers weredried over anhydrous Na₂SO₄ then evaporated under reduced pressure.Purification of the resulting crude product by flash silica gelchromatography provided the dihydroxybenzene sulfonyl chloride (246 mg,50%) as an oil. ¹H NMR (CDCl₃, 200 MHz): δ 7.1 (m, 2H), 6.8 (m, 1H).

The dihydroxy compound (222 mg, 1.06 mmol), DHP (224 mg, 2.66 mmol) inCH₂Cl₂ (10 mL), and PPTS (50 mg) were stirred for 30 minutes at roomtemperature. Then the reaction mixture was diluted with CH₂Cl₂ (20 mL),and the organic layer washed with brine (2×20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and evaporated under reducedpressure. Purification of the resulting crude product by flash silicagel chromatography provided the compound 39 (237 mg, 67%) as an oil. ¹HNMR (CDCl₃, 300 MHz): δ 7.3 (m, 2H), 7 (m, 1H), 5.4 (m, 2H), 3.8 and 3.6(two m, 4H), 1.4–2 (m, 12 H).

5-Nitropyridine-3-sulfonyl chloride (42)

Key: (a) Br₂, 130° C., 8 hours; (b) H₂O, 100° C., 2 hours; (c) NH₄OH,CuSO₄.5H₂O, 170° C., 20 hours; (d) fuming H₂SO₄, H₂O₂, 0° C.-23° C., 40hours; (e) PCl₅, POCl₃, reflux, 6 hours, 45% for five steps.

5-Bromopyridine-3-sulfonic acid (41)

Compound 40 (7 g, 35 mmol) and bromine (6.7 g, 42 mmol) in a sealed tubewere heated at 130° C. for 8 hours on oil bath. After cooling to roomtemperature, water (70 mL) was added, and the reaction mixture heatedagain at 100° C. for 2 hours. After cooling, acetone (60 mL) was addedand resulting solid was filtered, and dried to obtain compound 41 ascrude product white solid. ¹H NMR (dMSO-d₆, 300 MHz): δ 9.3 (br s, 1H),8.8 (m, 2H), 8.2 (m, 1H).

5-Nitropyridine-3-sulfonyl chloride (42)

The acid 41 (4.5 g, 19 mmol), ammonium hydroxide (NH₄OH) (15 mL, 28%),and copper sulfate (CuSO₄.5H₂O) (470 mg, 1.9 mmol) were heated at 170°C. in a sealed tube for 20 hours. After cooling, water (5 mL) was addedfollowed by sodium sulfide (Na₂S.9H₂O) (450 mg). Evaporation of watergave the crude aminopyridinesulfonic acid.

Fuming H₂SO₄ (30 mL) was placed in a flask cooled to 0° C. Hydrogenperoxide (H₂O₂) (14 mL, 30%) was carefully added. Then, the above crudesulfonic acid (2.8 g, 16 mmol) in H₂SO₄ (8 mL) was added to the abovemixture. The resulting solution was stirred at room temperature, for 40hours, and then poured into ice water-containing sodium carbonate(Na₂CO₃). Sufficient Na₂CO₃ was added to make the solution basic, whichwas acidified again to pH 1–2. The resulting solution was concentratedto minimum volume (20 mL). The precipitated NaCl was filtered, and thefiltrate was concentrated. The resulting solid was extracted with MeOH(3×50 mL). The combined MeOH extractions were concentrated to 20 mL, andacetone (80 mL) was added. The solid obtained was filtered and dried toobtain nitropyridine sulfonic acid.

This acid (1.7 g, 7 mmol) and phosphorus pentachloride (PCl₅) (1.7 g, 8mmol) in POCl₃ (50 mL) were refluxed for 6 hours. After cooling to roomtemperature, the solids were filtered, and the filtrate concentrated.The oily residue was diluted with EtOAc (100 mL) and the organic layerwashed with brine (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and evaporated to obtain compound 42 (730 mg, 45%) asan oil. ¹H NMR (CDCl₃, 400 MHz): δ 9.15 (m, 1H), 9.02 (m, 1H), 8.43 (m,1H).

4-Fluoro-3-nitrobenzenesulfonyl chloride (44)

Key: (a) fuming H₂SO₄, 60° C., 30 min, quantitative; (b) PCl₅, POCl₃,reflux, 6 hours, quantitative.

To compound 43 (7 g, 5 mmol) was carefully added fuming H₂SO₄ (60 mL).The resulting mixture was heated to 60° C. for 30 minutes. Then, the hotmixture was slowly and very carefully poured into beaker containingpotassium chloride (KCl) (30 g) and ice. The resulting white solidobtained was recrystallized from hot water to give4-fluoro-3-nitrobenzenesulfonic acid in quantitative yield.

The acid (2 g, 7.7 mmol) and phosphorus pentachloride (PCl₅) (1.8 g, 7.5mmol) in phosphorus oxytrichloride (POCl₃) (60 mL) were refluxed for 6hours. The resulting mixture was cooled to room temperature, andconcentrated. Crushed ice was added to the oily residue. The solid wasfiltered and washed with water (2×50 mL), dried to obtain compound 44(quantitative). ¹H NMR (CDCl₃, 500 MHz): δ 8.8 (m, 1H), 8.36 (m, 1H),7.6 (m, 1H).

Synthesis of Pyrrolidine Amines (46) and (50)

Key: (a) Boc₂O, CH₂Cl₂, 2 hours; (b) p-TsCl, Et₃N, DMAP, CH₂Cl₂, 8hours, quantitative; (c) NaN₃, DMF, 80° C., 4 hours; (d) H₂, Pd—C (10%);MeOH, 5–6 hours, 92%.

(3R)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (46)

Compound 45 (775 mg, 9 mmol) and Boc₂O (2:33 g, 10.6 mmol) in CH₂Cl₂ (40mL) were stirred for 2 hours at room temperature. Then the reactionmixture was diluted with CH₂Cl₂ (20 mL), and the organic layer washedwith brine (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated. Purification of the resulting crudeproduct by flash silica gel chromatography provided N-Boc pyrrolidnol asan oil.

This alcohol (7.3 g, 39 mmol), p-TsCl (8.2 g, 43 mmol), Et₃N (9.8 g, 97mmol), DMAP (240 mg) in CH₂Cl₂ (100 mL) were stirred for 8 hours at roomtemperature. Then the reaction mixture was washed with brine (100 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated.Purification of the resulting crude product by flash silica gelchromatography provided the ester in quantitative yield.

This sulfonate ester (12.5 g, 38 mmol) and NaN₃ (3.7 g, 57 mmol) in DMF(70 mL) were heated at 80° C. for 4 hours. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc (200 mL). Theorganic layer washed with brine (2×100 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated. Purification of theresulting crude product by flash silica gel chromatography provided theazido compound, which was hydrogenated in presence of Pd—C (10%) in MeOHfor 5–6 hours to obtain compound 46 (7.43 g, 92%) as an oil. ¹H NMR(CDCl₃, 300 MHz): δ 4.12 (m, 1H), 3.5 (m, 4H), 2 (m, 2H), 1.45 (s, 9H).

Key: (a) LiAlH₄, THF, 55° C., 24 hours, 55%; (b) MsCl, Et₃N, CH₂Cl₂, 0°C., 45 min, 90%; (c) BnNH₂, reflux, 36 hours; (d) Pd(OH)₂, Boc₂O, Et₃N,THF, 8 hours, 85%; (e) TsOH, MeOH, 1 hour 96%; (f) MsCl, Et₃N, 0° C.,CH₂Cl₂, 10 min.; (g) NaN₃, DMF, 80° C., 6 hours; (h) H₂, Pd—C (10%),MeOH, 5–6 hours, 81% for two steps.

Methanesulfonic acid4-methanesulfonyloxy-3-(tetrahydropyran-2-yloxy)butyl ester (48)

To compound 47 (8.4 g, 34 mmol) in THF (130 mL) was added lithiumaluminum hydride (LiAlH₄) (7.6 g, 206 mmol) in portions. The resultingmixture was heated at 55° C. for 24 hours. After cooling to roomtemperature, H₂O (7.2 ml), NaOH (7.2 mL, 20%), and H₂O (14.4 mL) wereadded sequentially and the mixture was stirred for 12 hours. The solidwas filtered and the filtrate concentrated. Purification of theresulting crude product by flash silica gel chromatography provided thediol (3.66, 55%) as an oil. ¹H NMR (CDCl₃, 400 MHz): δ 4.6 (m, 1H), 4(m, 1H), 3.5–3.9 (m, 6H), 2.92 (s, 2H), 1.4–1.82 (m, 8H), (s, 9H).

To that diol (3.66 g, 19 mmol) and Et₃N (5.23 g, 51 mmol) in CH₂Cl₂ (80mL) at 0° C. was added MsCl (5.48 g, 48 mmol). The resulting reactionmixture was stirred for 45 minutes at room temperature, then thereaction mixture was diluted with CH₂Cl₂ (50 mL) and the organic layerwashed with brine (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated. Purification of the resulting crudeproduct by flash silica gel chromatography provided the compound 48 (6g, 90%) as an oil. ¹H NMR (CDCl₃, 300 MHz): δ 4.6 (m, 1H), 4.2–4.4 (m,4H), 3.8–4.1 (m, 2H), 3 (m, 6H.), 2 (m, 2H), 1.75 (m, 2H), 1.45 (m, 4H).

3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (49)

Compound 48 (6 g, 17 mmol) and BnNH₂ (6.5 g, 60 mmol) in THF (150 mL)were refluxed for 12 hours. Then, benzylamine (BnNH₂) (6.5 g, 60 mmol)again was added and refluxing was continued for 24 hours, followed bycooling to room temperature. The reaction mixture was diluted with EtOAc(100 mL) and the organic layer washed with brine (2×20 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated.Purification of the resulting crude product by flash silica gelchromatography provided the pyrrolidine compound (4.4 g) as an oil. ¹HNMR (CDCl₃, 300 MHz): δ 7.2 (m, 5H), 4.55 (m, 1H), 4.38 (m, 1H), 3.8 (m,1H), 3.6 (m, 2H), 3.41 (m, 1H), 2.4–2.7 (m, 4H), 2.1 (m, 1H), 1.4–1.9(m, 7H).

This amino compound (4.4 g, 17 mmol) in MeOH (50 mL) was hydrogenatedover Pd(OH)₂ (1 g, 20%) for 18 hours. Boc₂O (4.4 g, 20 mmol) and Et₃N (3g, 21 mmol) were added and stirred for 8 hours at room temperature. Thereaction mixture was diluted with EtOAc (100 mL) and the organic layerwashed with brine (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated. Purification of the resulting crudeproduct by flash silica gel chromatography provided the Boc compound(3.9 g, 85%).

To this THP ether (3.9 g, 14.3 mmol) in MeOH (60 mL) was added TsOH (140mg), followed by stirring for 1 hour at room temperature Then thereaction mixture was diluted with EtOAc (100 mL) and the organic layerwashed with brine (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated. Purification of the resulting crudeproduct by flash silica gel chromatography provided compound 49 (2.56,96%). [α]_(D) ²⁵: +24.2°, c, 2.1; CHCl₃. ¹H NMR (CDCl₃, 300 MHz): δ 4.4(m, 1H), 3.4 (m, 3H), 3.3 (m, 1H), 1.89 (m, 2H), 1.4 (m, 9H).

(3S)-3-Aminopyrrolidine-1-carboxylic acid tert-butyl ester (50)

To compound 49 (g, 10.7 mmol) and Et₃N (2.15 g, 21 mmol) in CH₂Cl₂ (50mL) at 0° C. was added MsCl (1.46 g, 12.8 mmol), followed by stirringfor 10 minutes room temperature. Then the reaction mixture was dilutedwith CH₂Cl₂ (50 mL) and the organic layer washed with brine (2×50 mL).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated. Purification of the resulting crude product by flashsilica gel chromatography provided the dimesolate compound (2.9 g) as anoil.

This mesolate (2.9 g, 11 mmol) and NaN₃ (1 g, 16 mmol) in DMF (20 mL)were stirred for 6 hours at 60° C. Then the reaction mixture was dilutedwith EtOAc (50 mL) and the organic layer washed with brine (2×20 mL).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated. Purification of the resulting crude product by flashsilica gel chromatography provided an azido compound, which washydrogenated as described above to provide compound 50 (1.87 g, 81%) asan oil. ¹H NMR (CDCl₃, 400 MHz): δ 4.12 (m, 1H), 3.4 (m, 4H), 2 (m, 2H),1.45 (s, 9H).

3-Aminoazetidine-1-carboxylic acid tert-butyl ester (53)

Key: (a) benzhydrylamine, MeOH, 72 hours, 23° C., then reflux 72 hours;(b) MeOH, EtOH (1:1), Pd(OH)₂ (20%), 12 hours; (c) Boc₂O, sat. NaHCO₃,24 hours; (d) MsCl, Et₃N, CH₂Cl₂, 1 hour, 83%; (e) NaN₃, DMF, 70° C., 72hours, then H₂, Pd—C (10%), MeOH, 5–6 hours, quantitative.

3-Hydroxyazetidine-1-carboxylic acid tert-butyl ester (52)

2-(2-Chloroethyl)oxirane (51) (5 g, 54 mmol) and benzhydrylamine (10 g,53 mmol) in MeOH (25 mL) were allowed to stand for 72 hours, thenrefluxed for 72 hours. The reaction mixture was cooled to roomtemperature, then concentrated to obtain a crude product solid.

The crude product (1.7 g, 7 mmol), in MeOH and EtOH (10+10 mL), washydrogenated in presence of Pd(OH)₂ (500 mg, 20%) for 12 hours. Thereaction mixture then was filtered, and Boc₂O (2.3 g, 10 mmol) and sat.NaHCO₃ solution (10 mL) were added, followed by stirring for 24 hours atroom temperature. Then the reaction mixture was diluted with EtOAc (50mL) and the organic layer washed with brine (2×20 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated.Purification of the resulting crude product by flash silica gelchromatography provided compound 52 (1.35 g). ¹H NMR (CDCl₃, 300 MHz): δ4.5 (m, 1H), 4.04 (m, 2H), 3.7 (dd, 2H), 1.45 (s, 9H).

3-Aminoazetidine-1-carboxylic acid tert-butyl ester (53)

To compound 52 (928 mg, 5.3 mmol) and Et₃N (1 g, 10.7 mmol) in CH₂Cl₂(20 mL) was added MsCl (733 mg, 6.4 mmol), followed by stirring for 1hour at room temperature. Then the reaction mixture was diluted withCH₂Cl₂ (20 mL) and the organic layer washed with brine (20 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentrated.Purification of the resulting crude product by flash silica gelchromatography provided the mesolate compound (1.11 g, 83%) as an oil.

The mesolate (1.11 g, 4.4 mmol) and NaN₃ (574 mg, 8.8 mmol) in DMF (10mL) were stirred for 72 hours at 72° C. Then the reaction mixture wasdiluted with EtOAc (20 mL), and the organic layer was washed with brine(2×20 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated. Purification of the resulting crude product by flashsilica gel chromatography provided the azido compound, which wassubsequently converted to compound 53 in quantitative yield byhydrogenation. ¹H NMR (CDCl₃, 300 MHz): δ 4.15 (m, 3H), 3.82 (m, 2H),1.4 (s, 9H).

3-Aminotetrahydrofuran (55)

Key: (a) MsCl, Et₃N, CH₂Cl₂, 1 hour; (b) NaN₃, DMF, 70° C., 72 hours;(c) H₂, Pd—C (10%), MeOH, 5–6 hours, quantitative.

The same reaction conditions used to prepare compound 53 were used toobtain compound 55 in quantitative yield. A satisfactory NMR wasobtained for this compound.

3,5-Bis-(tetrahydropyran-2-yloxy)benzenesulfonyl chloride (57)

Key: (a) aminosulfonic acid, 180–200° C., 1.5 hours, 40%; (b) SO₂Cl,reflux, DMF, 1 hour, 44%; (c) DHP, PPTS, CH₂Cl₂, 2 hours, 56%.

Compound 56 (25 g, 220 mmol) was heated at 180–200° C., thenaminosulfonic acid (9.7 g, 100 mmol) was added portion wise. Theresulting slurry was stirred and heated for 1.5 hours, then cooled, anddissolved in minimum amount of water. The clear solution was treatedwith decolorizing charcoal and filtered. The filtrate was washed withether (2×50 mL), and the aqueous layer concentrated to minimum volume(20 mL). Upon standing crystals separated which were dried to obtain3,4-dihydroxybenzene sulfonic acid (7.56 g, 40%). M.P.: 254–255° C.,lit. 260° C.

To the above sulfonic acid (7 g, 38 mmol), was added SOCl₂ (15 mL) andDMF (0.1 mL) following the same conditions described above for compound39 to obtain the sulfonyl chloride (3.6 g, 44%) as an oil.

This chloride (3.5 g, 16.8 mmol), DHP (3.1 g, 37 mmol) and PPTS (200 mg)in CH₂Cl₂ (50 mL) were stirred for 2 hours at room temperature. Then thereaction mixture was diluted with CH₂Cl₂ (20 mL) and the organic layerwashed with NaHCO₃ (20 mL), then brine (2×20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedcompound 57 (3.2 g, 56%) as an oil. ¹H NMR (CDCl₃, 200 MHz): δ 8 (d, 1H,J=2 Hz), 7.63 (m, 1H), 7.25 (d, 1H, J=8.4 Hz), 5.58 (m, 2H,), 3.4–4.2(m, 4H), 1.4–2.2 (m, 12H).

Synthesis of Mixed Carbonates of Spirocycles

Key: (a) DHP, PPTS, CH₂Cl₂, 4–5 hours; (b) K₂CO₃, MeOH, 30 min.; (c)Rh/Al₂O₂, H₂, EtOAc, 8–12 hours; (d) BnBr, NaH, TBAI, THF, 12–14 hours;(e) p-TsOH, MeOH, 20–30 min.; (f) PCC, CH₂Cl₂, MS (4 Å), 12 hours; (g)allylmagnesium bromide, THF, 0° C., 30 min.; (h) 9BBN, THF, roomtemperature 24 hours; (i) MsCl, Py, 24 hours; (j) H₂, Pd(OH)₂, EtOAc, 12hours; (k) N,N-disuccinimidyl carbonate, Et₃N, acetonitrile, 12–24hours.

Same conditions were followed for the synthesis of mixed carbonate 63.

Variation of p2 Ligands of the 3-hydroxybenzene Sulfonamide Isostere

Key: (a) Isobutylamine, isopropanol, reflux, 6 hours; (b) sulfonylchloride 33, CH₂Cl₂, aq. NaHCO₃ sol., 12 hours; (c) Pd—C (10%), H₂,MeOH, 6–8 hours; (d) various mixed carbonates, Et₃N, CH₂Cl₂, 4–6 hours.

Activity IC₅₀ Ki No. (nM) (nM) 75

6.7 2.1 78

1.6 53 79

5.5 1.7

Compound 75: Compound 66 (0.12 mmol), compound 26 (0.14 mmol), and Et₃N(2 equiv.) in CH₂Cl₂ (1 mL) were stirred for 6 hours at roomtemperature. Then the reaction mixture was diluted with CH₂Cl₂ (10 mL)and the organic layer washed with brine (2×20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedthe THP ether.

The THP ether (0.011 mmol) and p-TsOH (2 mg) in MeOH (0.5 mL) werestirred for 10 minutes at room temperature. Then the reaction mixturewas diluted with EtOAc (10 mL) and the organic layer washed with brine(2×20 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated. Purification of the resulting crude product by flashsilica gel chromatography provided compound 75 (5 mg) as a solid. ¹H NMR(CDCl₃, 400 MHz): δ 8.3 (s, 1H), 7–7.4 (m, 9H), 5.05 (m, 1H), 4.68 (d,1H, 4Hz), 3.8–4 (m, 3H), 3.6 (m, 1H), 2.6–3.1 (m, 6H), 1.5–2.1 (m, 1H),0.93 (m, 6H).

Compound 78: Compound 66 (22 mg, 0.055 mmol), compound 4 (18 mg, 0.066mmol), and Et₃N (2 equiv.) in CH₂Cl₂ (1 mL) were subjected to sameconditions as described above for compound 75 to obtain compound 78 (23mg) as a solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.2–7.5 (m, 9H), 5.5 (m, 1H),4.86 (m, 2H), 4.4 (m, 1H), 3.6–3.8 (m, 6H), 2.8–3.2 (m, 6H), 2.6 (m,1H), 1.4–2.1 (m, 13H), 0.96 (ABq, 6H, J=6.5 Hz).

Compound 79: Compound 78 (19 mg, 0.03 mmol) and TsOH (6 mg) in MeOH (1mL) were subjected to same conditions as described above for compound 75to obtain compound 79 (12 mg) as a solid. ¹H NMR (CDCl₃, 400 MHz): δ 8.9(s, 1H), 7.1–7.4 (m, 8H), 7.03 (d, 1H, J=6.9 Hz), 5.29 (m, 1H), 5 (d,1H, J=8.8 Hz), 4.6 (t, 1H, J=6.1 Hz), 4.1 (m, 1H), 3.85–4 (m, 2H), 3.75(q, 1H, J=7.9 Hz), 3.53 (dd, 1H, J=3 Hz, 15 Hz), 3.1 (m, 1H), 2.91 (dd,1H, J=5.2 Hz, 14 Hz), 2.82 (m, 1H), 2.65 (dd, 1H, J=7.6 Hz, 14.9 Hz),2.59 (dd, 1H, J=4.6 Hz, 13.1 Hz), 1.7–2.2 (m, 7H), 0.98 and 0.88 (ABq,6H, J=6.4 Hz).

Variation of p2 Ligands of 2,4-dihydroxybenzene Sulfonamide Isostere

Key: a) Isobutylamine, isopropanol, reflux, 6 hours; b) sulfonylchloride 39, CH₂Cl₂, aq. NaHCO₃ sol., 12 hours; c) Pd—C (10%), H₂, MeOH,6 hours; d) mixed carbonate, Et₃N, CH₂Cl₂, 2–3 hours; e) p-TsOH, MeOH,5–15 minutes.

Activity IC₅₀ Ki No. (nM) (nM) 87

30 9.3 88

3.9 1.2

Compound 87: Compound 80 (55 mg, 0.9 mmol), compound 4 (25 mg, 0.9mmol), and Et₃N (2.0 equiv.) in CH₂Cl₂ (2 mL) were subjected to sameconditions as described above for compound 75 to obtain compound 87 (26mg) as a solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.2–7.5 (m, 8H), 5.56 (m,2H), 4.86 (m, 2H), 4.3 (m, 1H), 3.5–4 (m, 8H), 2.8–3.2 (m, 6H), 2.6 (m,1H), 1.6–2.1 (m, 19H), 0.86 (ABq, 6H, J=6.3 Hz).

Compound 88: Compound 87 (21 mg, 0.028 mmol) and p-TsOH (10 mg) in MeOH(1 mL) were subjected to same conditions as described above for compound75 to obtain compound 88 (8 mg) as a solid. M.P.: 80–82° C. [α]_(D) ²⁵:+9.7°, c, 0.82, MeOH. ¹H NMR (CDCl₃, 400 MHz): δ 9.5 (s, 1H), 7.2 (m,7H), 7 (d, 1H, J=8.3 Hz), 6 (s, 1H), 5.03 (t, 1H, J=5.2 Hz), 4.91 (d,1H, J=8.9 Hz), 4.58 (t, 1H, J=6.2 Hz), 4.18 (dd, 1H, J=6.5 Hz, 7.7 Hz),3.9 (m, 2H), 3.82 (m, 1H), 3.51 (dd, 1H, J=3.5 Hz, 15 Hz), 3.25 (m, 1H),3.1 (m, 2H), 2.95 (dd, 1H, J=8.2 Hz, 14 Hz), 2.87 (m, 1H), 2.58 (m, 1H),2.49 (dd, 1H, J=4.3 Hz, 13 Hz), 1.9–2.2 (m, 4H), 1.75 (d, 1H, J=14.2Hz), 1.02 and 0.87 (ABq, 6H, 6.4 Hz).

Variation of p2 Ligands of 3,5-dihydroxybenzene Sulfonamide Isostere

Key: a) Isobutylamine, isopropanol, reflux, 6 hours; b) sulfonylchloride 39. aqueous NaHCO₃, CH₂Cl₂, 12 hours; c) Pd—C (10%), H₂, MeOH,6 hours; d) various mixed carbonates, Et₃N, CH₂Cl₂, 6 hours; e) p-TsOH,MeOH, 5–15 min.

Activity IC₅₀ Ki No. (nM) (nM) 99

3.9 1.2 100

247 77

Compound 99: Compound 89 (102 mg, 0.178 mmol), compound 4 (48 mg, 0.178mmol), and Et₃N (2.0 equiv.) in CH₂Cl₂ (5 mL) were subjected to sameconditions as described above for compound 75 to obtain compound 99 (110mg) as a solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.25 (m, 5H), 7.09 (s, 2H),6.96 (s, 1H), 5.43 (m, 2H), 4.78 (m, 2H), 4.39 (m, 1H), 3.9 (m, 5H),3.65 (m, 3H), 3.15 (m, 2H), 3.05 (m, 1H), 2.87 (m, 2H), 2.6 (m, 1H),2.02, 1.85 and 1.7 (three m, 18H), 0.92 and 0.87 (ABq, 6H, J=6.4 Hz).

Compound 100: Compound 99 (88 mg, 0.12 mmol) and TsOH (20 mg) in MeOH (5mL) were subjected to same conditions as described above for compound 75to obtain compound 100 as a solid. ¹H NMR (CDCl₃, 200 MHz): δ 8.08 (s,2H), 7.23 (m, 5H), 6.78 (s, 2H), 6.54 (s, 1H), 5.21 (d, 1H, J=8 Hz),4.93 (m, 1H), 4.52 (m, 1H), 3.8–4.1 (m, 3H), 3.68 (dd, 1H, J=7 Hz, 14.5Hz), 3.5 (m, 2H), 2.5–3.1 (m, 7H), 1.5–2.2 (m, 7H), 0.92 and 0.89 (ABq,6H, J=6.4 Hz).

Incorporation of High Affinity p2 Ligands to New Class ofHydroxyethylamine Isostere

Key: a) Isobutylamine, isopropanol, reflux, 6 hours; b) sulfonylchloride 35, aqueous NaHCO₃, CH₂Cl₂, 12 hours; c) K₂CO₃, MeOH, 30 min;d) NaBH₄, MeOH, 15 min; e) Pd—C (10%), H₂, MeOH, 6 hours; f) variousmixed carbonates, Et₃N, CH₂Cl₂, 6 hours.

Activity No. IC₅₀ (nM) 110

1.3 111

2.9 113

4.0 114

1.1

Compound 110: Compound 101 (70 mg, 0.17 mmol), compound 4 (46 mg, 0.17mmol), and Et₃N (2.0 equiv.) in CH₂Cl₂ (10 mL) were subjected to sameconditions as described above for compound 75 to obtain compound 110 (75mg) as a solid. M.P.: 110–112° C. [α]_(D) ²⁵: +10°, c, 0.72, CHCl₃. ¹HNMR (CDCl₃, 400 MHz): δ 7.75 (d, 2H), 7.5 (d, 2H), 4.85 (s, 1H), 4.76(m, 3H), 4.37 (m, 1H), 3.6–3.9 (m, 4H), 2.8–3.15 (m, 6H), 2.6 (m, 1H), 2(m, 2H), 1.8 (m, 2H), 1.69, 1.55, and 1.44 (three m, 3H), 0.89 (ABq, 6H,J=6.4 Hz).

Compound 111: Compound 101 and compound 6 were subjected to conditionspreviously described above for compound 75 to obtain 111 as a solid: ¹HNMR (CDCl₃, 300 MHz): δ 7.76 (d, 2H, J=8 Hz), 7.42 (d, 2H, J=8.1 Hz),7.2 (m, 5H), 4.8 (m, 1H), 4.77 (s, 2H), 4.66 (m, 1H), 4.35 (m, 1H),3.6–3.82 (m, 4H), 2.71–3.05 (m, 6H), 2.6 (m, 1H), 1.4–2.1 (m, 6H), 0.82(ABq, 6H, J=6.4 Hz).

Compound 113: Compound 112 and compound 4 were subjected to conditionsdescribed above for compound 75 to obtain 113 as a solid. [α]_(D) ²⁵:+4.4° C., c, 0.67, CHCl₃. ¹H NMR (CDCl₃, 300 MHz): δ 7.8 (s, 1H), 7.61(d, 1H, J=10 Hz), 7.44 (m, 2H) 7.21 (m, 5H), 4.92 (d, 1H, J=10.8 Hz),4.81 (m, 1H), 4.71 (s, 2H), 4.38 (m, 1H), 3.6–3.91 (m, 3H), 3.39 (m,1H), 3.01 (m, 3H), 2.92 (d, 2H, J=10 Hz), 2.5–2.8 (m, 2H), 1.78–2.02 (m,5H), 1.4–1.65 (m, 2H), 0.91 (ABq, 6H, J=6.3 Hz).

Compound 114: Compound 112 and compound 15 were subjected to conditionsas described above for compound 75 to obtain 114 as a solid. ¹H NMR(CDCl₃, 400 MHz): δ 7.15–7.65 (m, 9H), 5.6 (d, 1H, J=5.1 Hz), 5.54 (d,1H, J=9.2 Hz), 4.96 (m, 1H), 4.69 (s, 2H), 3.57–3.83 (m, 6H), 2.72–3.2(m, 7H), 1.9, 1.32 and 1.26 (three m, 3H), 0.88 (ABq, 6H, J=6.4 Hz).

Bis-THF as p2 Ligand in Hydroxyethylsulfonamide Isostere with Variationat p1¹ Region

Key: a) iBuNH₂, iPrOH, reflux, 6 hours; b) sulfonyl chloride 35 or 36,aq. NaHCO₃, CH₂Cl₂, 12 hours; c) Pd—C (10%), MeOH, 6–8 hours; d) K₂CO₃,MeOH, 30 min; c) H₂, Pd—C (10%), mixed carbonate 15; Et₃N, THF, 12hours; d) (i) NaBH₄, EtOH, (ii) TsCl, Et₃N, DMAP for compound 117; e)reductive amination (NaCNBH₄, AcOH, MeOH); with NH₄OAc for compound 118,with MeNH₂ for compound 119; f) NH₂OH; HCl, Et₃N, MeOH, for compound120; g) (i) triphenylphosphono-acetate, NaH, THF, 0° C., 30 min (ii)DIBAL-H, CH₂Cl₂, −78° C., 1 h for compound 121.

Activity IC₅₀ Ki No. Compound (nM) (nM) 117

2.4 0.74 118

2.7 0.9 119

3.5 1.1 120

2.4 0.74 121

3.0

Compound 117: Compound 116 was subjected to NaBH₄ reduction and theresulting alcohol was treated with pTsCl in pyridine to obtain compound117 as an oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.79 (d, 2H, J=8 Hz), 7.74 (d,2H, J=8.4 Hz), 7.43 (d, 2H, J=8 Hz), 7.36 (d, 2H, J=8.4 Hz), 7.23 (m,5H), 5.64 (d, 1H, J=5.2 Hz), 5.1 (s, 2H), 5.02 (m, 2H), 3.8–4 (m, 3H),3.7 (m, 2H), 3.61 (m, 1H), 2.75–3.2 (m, 7H), 2.45 (s, 3H), 1.45, 1.6,and 1.83 (three m, 3H), 0.89 (ABq, 6H, J=6.4 Hz).

Compound 118: Compound 117 (26 mg, 0.036 mmol) and NaN₃ (5 mg, 0.073mmol) in DMF (2 mL) were stirred for 30 min at 65–70° C. Then thereaction mixture was diluted with EtOAc (20 mL) and the organic layerwashed with brine (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated. Purification of the resulting crudeproduct by flash silica gel chromatography provided an azidointermediate.

The azido intermediate (21 mg, 0.036 mmol) and triphenylphospine (Ph₃P)(14 mg, 0.054 mmol) in THF.H₂O (9:1, 2 mL) were stirred for 12 hours atroom temperature. Then the reaction mixture was diluted with EtOAc (20mL) and the organic layer washed with brine (2×20 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated.Purification of the resulting crude product by flash silica gelchromatography provided compound 118 as a solid. ¹H NMR (CDCl₃, 200MHz): δ 7.75 (d, 2H, J=8.2 Hz), 7.51 (d, 2H, J=8 Hz), 7.23 (m, 5H), 5.65(d, 1H, J=5.2 Hz), 4.99 (m, 2H), 3.62–4.1 (m, 6H), 2.73–3.2 (m, 7H),1.85 (m, 1H), 1.6 (m, 2H), 0.91 (ABq, 6H, J=6.4 Hz).

Compound 119: To compound 116 (75 mg, 0.133 mmol), methylamine (MeNH₂)(8.3 mg, 0.026 mmol), and acetic acid (ACOH) (9.5 mg, 0.015 mmol) inMeOH (5 mL) was added sodium cyanoborohydride (NaCNBH₄) (10 mg, 0.159mmol) at room temperature. The resulting reaction mixture was stirredfor 12 hours at room temperature. Then the reaction mixture was dilutedwith EtOAc (20 mL) and NaHCO₃ solution (5 mL). The organic layer washedwith brine. (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated. Purification of the resulting crudeproduct by flash silica gel chromatography provided compound 119 as asolid. M.P.: 57–62° C. ¹H NMR (CDCl₃, 400 MHz): δ 7.75 (d, 2H, J=7.6Hz), 7.75 (d, 2H, J=8 Hz), 5.64 (d, 1H, J=5.2 Hz), 5.03 (m, 2H), 3.8–4(m, 5H), 3.88 (s, 2H), 3.67 (m, 1H), 2.75–3.2 (m, 7H), 1.44, 1.63, and1.93 (three m, 3H), 0.89 (ABq, 6H, J=6.4 Hz).

Compound 120: The above azido epoxide was converted into thecorresponding aldehyde using the following sequence: i) terminal epoxideopening with isobutylamine in isopropyl alcohol for 3 hours; ii)treatment of resulting amine with compound 37 in NaHCO₃/H₂O; and iii)hydrolysis of the resulting bis-acetoxy compound using K₂CO₃ in MeOH toobtain the aldehyde. The resulting aldehyde (35 mg, 0.062 mmol),hydroxylamine hydrochloride (NH₂OH.HCl) (86 mg, 0.12 mmol), and Et₃N (2eq) in MeOH (5 mL) were stirred for 24 hours at room temperature. Thenthe reaction mixture was diluted with EtOAc (20 mL) and the organiclayer washed with brine (2×20 mL). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated. Purification of the resultingcrude product by flash silica gel chromatography provided the azidooxime as an oil.

The azido function of the oxime was hydrogenated over Pd/C (10%) in MeOHfor 6 hours, and the resulting amine was treated with compound 15 (1eq.) and Et₃N (2 eq.) in CH₂Cl₂ for 3 hours to obtain compound 120 as asolid. ¹H NMR (CDCl₃, 400 MHz): δ 8.15 and 8.05 (two s, 2H), 7.77 (d,1H, J=7.6 Hz), 7.72 (d, 1H, J=7.6 Hz), 7.54 (dd, 1H, J=7.6 Hz, 8.0 Hz),5.67 (d, 1H, J=5.2 Hz), 5.05 (m, 2H), 3.7–4 (m, 6H), 3.19 (m, 1H), 3.1(m, 2H), 2.95 (d, 2H, J=7.6 Hz), 2.8 (dd, 1H, J=7.6 Hz, 12.4 Hz), 1.6,1.7, and 1.85 (three m, 3H), 0.89 (d, 6H, J=6.4 Hz).

Compound 121: To (EtO)₂P(O)CH₂CO₂Et (1.1 equiv.) in THF was added NaH(37 mg, 0.93 mmol), followed by stirring for 10 hours at roomtemperature. Then aldehyde 116 (222 mg, 0.54 mmol) in THF (2 mL) wasadded and stirring was continued for 10 minutes at room temperature. Thereaction mixture was diluted with EtOAc (20 mL) and the organic layerwashed with brine (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated. Purification of the resulting crudeproduct by flash silica gel chromatography provided an ester. To theester (50 g, 0.1 mmol) in CH₂Cl₂ (5 mL) was added DIBAL-H(diisobutylaluminum hydride) (1M, 0.5 mL) at −78° C. After 30 min, thereaction mixture was warmed to room temperature, then treated with MeOH(1 mL) to destroy excess DIBAL-H. Cold dil. hydrochloric acid (HCl)(10%, 15 mL) was added cautiously and the resulting mixture was stirreduntil a clear organic layer was obtained which was extracted with EtOAc(2×10 mL). The organic layer washed with brine (2×20 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated to obtaina crude product amino allylic alcohol.

The amino alcohol (1 equiv.), compound 15 (1 equiv.), and Et₃N (2equiv.) in CH₂Cl₂ were stirred for 3 hours at room temperature. Then thereaction mixture was diluted with EtOAc and the organic layer washedwith brine. The combined organic layer was dried over anhydrous Na₂SO₄and concentrated. Purification of the resulting crude product by flashsilica gel chromatography provided compound 121 as a solid. ¹H NMR(CDCl₃, 400 MHz): δ 7.72 (d, 2H, J=8 Hz), 7.5 (d, 2H, J=8 Hz), 7.29 (m,5H), 6.69 (d, 1H, J=16 Hz), 6.51 (m, 1H), 5.6 (d, 1H, J=5.2 Hz), 5 (m,1H), 4.95 (d, 1H, J=8.4 Hz), 4.37 (d, 2H, J=4.4 Hz), 3.86 (m, 4H), 3.65(m, 2H), 3.15 (m, 1H), 3.1 (dd, 1H, J=4 Hz, 14.4 Hz), 3 (m, 2H), 2.81(m, 2H), 1.45, 1.61, and 1.8 (three m, 3H), 0.91 (ABq, 6H, J=6.4 Hz).

Key: a) iBuNH₂, iPrOH, reflux, 6 hours; b) sulfonyl chloride 35, aq.NaHCO₃, CH₂Cl₂, 12 hours; c) H₂, Pd—C (10%), mixed carbonate 4, Et₃N,THF, 12 hours; d) K₂CO₃, MeOH, 30 min; e) reductive amination (NaCNBH₄,AcOH, MeOH); with NH₄OAc for compound 125, with MeNH₂ for compound 126,with dimethylamine (Me₂NH) for compound 127; f) NH₂OH.HCl, Et₃N, MeOH,for compound 128; g) RSO₂Cl, where R is 4-hydroxymethylsulfonylchloride, or TsCl, or 8-quinoline sulfonyl chloride, or benzylsulfonylchloride, aq. NaHCO₃, CH₂Cl₂, 12 hours; h) Ph₃P, THF water, 12 hours.

IC₅₀ Ki No. Compound (nM) (nM) 125

3.5 1.1 126

15 127

50 128

1.7 0.53 129

2.9 0.9 130

0.8 131

1.4 132

12 3.7 133

48 15 134

3000 931

Compound 125: Compound 124 was converted into compound 125 using thefollowing reaction sequence: i) NaBH₄ reduction of aldehyde 124 toprimary alcohol; ii) tosylation of primary alcohol; iii) nucleophilicdisplacement of sulfonate ester with NaN₃/DMF/heat (65° C.); iv)conversion of the azido function to amine using Ph₃P/THF.H₂O (9:1)/12hours, to obtain compound 125. ¹H NMR (CDCl₃, 400 MHz): δ 7.74 (d, 2H,J=8.4 Hz), 7.48 (d, 2H, J=8.4 Hz), 7.3 (m, 5H), 4.9 (m, 2H), 4.41 (m,1H), 4 (s, 2H), 3.78 (m, 3H), 3.68 (m, 1H), 2.72–3.2 (m, 6H), 2.65 (m,1H), 2.46 (br s, 2H), 1.8–2.1 (m, 5H), 1.4 (m, 2H), 0.88 (ABq, 6H, J=6.4Hz).

Compound 126: Aldehyde 124 (50 mg, 0.89 mmol) and MeNH₂ (120 mg, 40% inwater) in MeOH (5 mL) were stirred in presence of hydrogen for 12 hoursat room temperature. Then the reaction mixture was filtered andconcentrated. Purification of the resulting crude product by flashsilica gel chromatography provided compound 126 (39 mg) as a solid. ¹HNMR (CDCl₃, 400 MHz): δ 7.73 (d, 2H, J=6.8 Hz), 7.47 (d, 2H, J=7.6 Hz),7.25 (m, 5H), 4.86 (m, 1H), 4.79 (d, 1H, J=7.6 Hz), 4.39 (t, 1H, J=6.4Hz), 3.82 (s, 2H), 3.82 (m, 3H), 3.7 (m, 1H), 3 (m, 4H), 2.8 (m, 2H),2.62 (m, 1H), 2.5 (s, 3H), 2 (m, 4H), 1.85 (m, 2H), 1.4 and 1.6 (two m,2H), 0.89 (ABq, 6H, J=6.4 Hz).

Compound 127: Aldehyde 124 (32 mg, 0.076 mmol) and HNMe₂ (0.09 mL, 0.019mmol) in MeOH (5 mL) was hydrogenated in presence of Pd—C (10%, 10 mg)for 12 hours. Filtration, followed by concentration, provided a crudeproduct. Purification of the resulting crude product by flash silica gelchromatography provided compound 127 (27 mg) as a solid. [α]_(D) ²⁵:+19.29, c 0.57, CHCl₃. ¹H NMR (CDCl₃, 200 MHz): δ 7.78 (d, 2H, J=8.2Hz), 7.58 (d, 2H, J=8.2 Hz), 7.25 (m, 5H), 4.84 (m, 2H), 4.39 (dt, 1H,J=6.4 Hz, 4.4 Hz), 3.6–3.85 (m, 6H), 2.75–3.2 (m, 6H), 2.6 (m, 1H), 2.38(s, 6H), 2 (m, 3H), 1.9 and 1.5 (two m, 4H), 0.88 (ABq, 6H, J=6.4 Hz).

Compound 128: Aldehyde 124 (137 mg, 0.339 mmol), NH₂OH.HCl (46 mg, 0.67mmol), and Et₃N (68 mg, 0.67 mmol) in MeOH (5 mL) were stirred for 12hours at room temperature. Then the reaction mixture was diluted withEtOAc (30 mL) and the organic layer washed with brine (2×20 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentrated.Purification of the resulting crude product by flash silica gelchromatography provided compound 128 (84 mg) as a solid. ¹H NMR (CDCl₃,300 MHz): δ 8.53 and 8.1 (two s, 2H), 7.73 (d, 2H, J=8.4 Hz), 7.65 (d,2H, J=8.7 Hz), 7.2 (m, 5H), 4.83 (m, 1H), 4.79 (d, 1H, J=8.7 Hz), 4.35(m, 1H), 3.78 (m, 3H), 3.61 (m, 1H), 2.75–3.12 (m, 6H), 2.6 (m, 1H),1.4, 1.8, and 2 (three m, total 7H), 0.83 (ABq, 6H, J=6.4 Hz).

Compound 129: Compound 37 was used in place of compound 35 in thereaction sequence as described for compound 124 to obtain correspondingmeta-substituted aldehyde in quantitative yield. The aldehyde wassubjected to similar conditions as described for compound 128 to obtaincompound 129 as a solid in quantitative yield. ¹H NMR (CDCl₃, 400 MHz):δ 9.5 (s, 1H), 8.1 (s, 2H), 7.77 (d, 1H, J=8 Hz), 7.62 (d, 1H, J=7.6Hz), 7.55 (t, 1H, J=4 Hz), 7.23 (m, 5H), 5.02 (d, 1H, J=8.8 Hz), 4.94(m, 1H), 4.44 (m, 1H), 3.6–4 (m, 4H), 3.4, 3, and 2.83 (three m, 6H),2.65 (m, 1H), 2.05 (m, 4H), 1.5, 1.63, and 1.9 (three m, 3H), 0.89 (ABq,6H, J=6.4 Hz).

Compound 130: To 4-bromobenzyl alcohol (1 equiv.) in THF was addedsodium hydride (NaH) (2 equiv.) at 0° C. To the resulting sodiumalkoxide, after 20 min, was added methyl iodide (MeI) (4 equiv.), andthe reaction mixture was allowed to stir for 24 hours at roomtemperature. After workup and purification, n-BuLi (2.1 equiv.) was usedto the resulting methyl ether derivative in THF at −78° C., followed bystirring for 1 hour. In another flask, SO₂Cl₂ (5 equiv.) in THF wascharged and cooled to −78° C. To this solution was added to the abovesolution. After one hour, workup with sat. NH₄Cl solution and flashchromatography, was provided p-methoxymethyl benzene sulfonyl chloridein 33% yield. After step (a) in the above scheme, the resulting amine (1equiv.), the above p-methoxymethyl benzene sulfonyl chloride (1.1equiv.) and Et₃N (2 equiv.) in CH₂Cl₂ were stirred for 12 hours at roomtemperature. Washing the reaction mixture with brine and sat. NH₄Cl, andpurification of crude residue, provided the corresponding sulfonamide.The azido function of the sulfonamide was converted to amine usingPh₃P/TH.H₂O (9:1)/12 hours. After purification, the resulting amine (1equiv.), active carbonate 4 (1.1 equiv.), and Et₃N (2 equiv.) in CH₂Cl₂were stirred for 2 hours at room temperature. Then the reaction mixturewas diluted with EtOAc and the organic layer washed with brine. Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentrated.Purification of the resulting crude product by flash silica gelchromatography provided compound 130 as liquid. ¹H NMR (CDCl₃, 400 MHz):δ 7.76 (d, 2H, J=8.4 Hz), 7.48 (d, 2H, J=8.4 Hz), 7.27 (m, 5H), 3.8 (m,3H), 3.63 (m, 1H), 3.43 (s, 3H), 3–3.15 (m, 3H), 2.95 (dd, 1H, J=13.6Hz, 8.4 Hz), 2.83 (m, 2H), 2.63 (m, 1H), 2.05 (m, 3H), 1.81 (m, 2H),1.49 and 1.55 (two m, 2H), 0.87 (ABq, 6H, J=6.4 Hz).

Compound 131: After step (a) in above scheme, the resulting amine (1equiv.) and TsCl (1.1 equiv.), in a mixture of sat. NaHCO₃ solution andCH₂Cl₂, were stirred for 12 hours at room temperature. Then the reactionmixture was extracted with EtOAc and the organic layer washed withbrine. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated. Purification of the resulting crude product by flashsilica gel chromatography provided the p-toluene sulfonamide derivative.The azido function of the above sulfonamide was hydrogenated in presencePd—C (10%) for 6 hours and the resulting amine (1 equiv.), activecarbonate 4 (1.1 equiv.), Et₃N (2 equiv.) in CH₂Cl₂ were stirred for 4hours at room temperature. Then the reaction mixture was diluted withEtOAc and the organic layer washed with brine. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedcompound 131 as solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.6 (d, 2H, J=8.4 Hz),7.31 (d, 2H, J=8 Hz), 7.25 (m, 5H), 4.87 (m, 1H), 4.75 (m, 1H), 4.4 (m,1H), 3.8 (m, 3H), 3.7 (m, 1H), 2.7–3.2 (m, 6H), 2.62 (m, 1H), 2.42 (s,3H), 2.03 (m, 3H), 1.82 (m, 2H), 1.4 and 1.53 (two m, 2H), 0.87 (ABq,6H, J=6.4 Hz).

Compound 132: After step (a) in the scheme above, the resulting amine (1equiv.) and commercially available 8-quinoline sulfonyl chloride (1.1equiv.) in a mixture of sat. NaHCO₃ solution and CH₂Cl₂ were stirred for12 hours at room temperature. Then the reaction mixture was diluted withEtOAc and the organic layer washed with brine. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedcorresponding 8-quinoline sulfoanmide derivative. The azido function ofthe above quinoline derivative (7 mg, 0.016 mmol) was hydrogenated inpresence of Pd—C (10%) in THF for 6 hours, and the resulting amine wastreated in situ with active carbonate 4 (4 mg, 0.016 mmol) and Et₃N (2equiv.) in CH₂Cl₂ (2 mL). The resulting mixture was stirred for 2 hoursat room temperature. Then the reaction mixture was diluted with EtOAcand the organic layer washed with brine. The combined organic layer wasdried over anhydrous Na2SO₄ and concentrated. Purification of theresulting crude product by flash silica gel chromatography providedcompound 132 (6.6 mg) as solid. ¹H NMR (CDCl₃, 300 MHz): δ 9.02 (dd, 1H,J=1.8 Hz, 3.9 Hz), 8.51 (dd, 1H, J=0.92 Hz, 7.2 Hz), 8.23 (dd, 1H, J=1.8Hz, 8.7 Hz), 8.03 (dd, 1H, J=0.9 Hz, 8.1 Hz), 7.6 (dd, 1H, J=7.5 Hz, 7.8Hz), 7.53 (dd, 1H, J=4.5 Hz, 8.4 Hz), 7.2 (m, 5H), 4.8 (m, 1H), 4.73 (d,1H, J=7.8 Hz), 4.34 (dd, 1H, J=5.4 Hz, 6.3 Hz), 3.76–3.92 (m, 3H), 3.6(m, 1H), 3.29 (d, 1H, 14 Hz), 3.02 (m, 3H), 2.91 (m, 2H), 2.62 (m, 1H),1.97 (m, 3H), 1.7 (m, 2H), 1.52 and 1.4 (two m, 2H), 0.65 (ABq, 6H,J=6.4 Hz).

Compound 133: After reaction step (a), the resulting amine (41 mg, 0.157mmol), commercially available benzyl sulfonyl chloride (1.1 equiv.), andEt₃N (2 equiv.) in CH₂Cl₂ (3 mL) were stirred for 12 hours at roomtemperature. Then the reaction mixture was diluted with EtOAc (20 mL)and the organic layer washed with brine (20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedthe corresponding sulfonamide. The above sulfonamide (38 mg, 0.091 mmol)and Ph₃P (47 mg, 0.18 mmol) in THF.H₂O (9:1) were stirred for 12 hoursat room temperature. Then the reaction mixture was diluted with EtOAc(20 mL) and the organic layer washed with brine (20 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated. Theresulting crude product amine, active carbonate 4 (25 mg, 0.93 mmol),and Et₃N (2 equiv.) in CH₂Cl₂ (5 mL) were stirred for 4 hours at roomtemperature. Then the reaction mixture was diluted with EtOAc (20 mL)and the organic layer washed with brine (20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedcompound 133 as solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.18–7.36 (m, 10H),4.9, 4.73, and 4.4 (three m, 3H), 4.27 (s, 2H), 3.72 (m, 4H), 3.05 and3.16 (two m, 2H), 2.81 (m, 5H), 1.5–2.1 (m, 7H), 0.84 ABq, 6, H, J=6.4Hz).

Compound 134: After reaction step (a), the resulting amine (1 equiv.),3,5-dihydroxybenzoic acid (1 equiv.), EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (1.2equiv.), HOBt (1-hydroxybenzotriazole hydrate) (1.2 equiv.), and Et₃N (4equiv.) in CH₂Cl₂.DMF (9:1) were stirred for 12 hours at roomtemperature. Then the reaction mixture was diluted with EtOAc and theorganic layer washed with brine. The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated. Purification of the resultingcrude product by flash silica gel chromatography provided corresponding3,5-dihydroxybenzamide derivative. The above derivative (1 equiv.) andactive carbonate 4 (1.1 equiv.) in THF were stirred under hydrogenatmosphere in presence of Pd—C (10%) for 12 hours at room temperature.Then the reaction mixture was filtered and the organic layer washed withbrine. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated. Purification of the resulting crude product by flashsilica gel chromatography provided compound 134 as a solid.

Key: a) Isobutylamine, isopropanol, reflux, 6 hours; b) sulfonylchloride 35, aq. NaHCO₃, CH₂Cl₂; c) K₂CO₃, MeOH, 30 min; d)N-methylpyrazine or morpholine, NaCNBH₄, AcOH, MeOH, 12 hours; e) TFA,CH₂Cl₂; f) mixed carbonate 22, Et₃N, CH₂Cl₂.

No. R₁ R₂ IC₅₀ (nM) 137

NMe 2100 138

NMe 270 139

0 968

Compound 137: ¹H NMR (CDCl₃, 400 MHz): δ 7.71 (d, 2H, J=8 Hz), 7.47 (d,2H, 8.4 Hz), 7.27 (m, 5H), 4.65 (d, 1H, J=8.4 Hz), 3.79 (m, 2H), 3.55(s, 2H), 2.8–3.12 (m, 6H), 2.5 (br m, 8H), 2.31 (s, 3H), 1.84 (m, 1H),1.33 (s, 9H), 0.9 (ABq, 6H, J=6.4 Hz).

Compound 138: Compound 125 was subjected to TFA.CH₂Cl₂ (20%) for 20 minat room temperature that provided a crude amine salt afterconcentration. The amine salt (8.7 mg), active carbonate 22 (5 mg), andEt₃N (2 equiv.) in CH₂Cl₂ (2 mL) were stirred for 4 hours at roomtemperature. Then the reaction mixture was diluted with EtOAc (20 mL)and the organic layer washed with brine (20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedcompound 138. ¹H NMR (CDCl₃, 400 MHz): δ 7.74 (d, 2H, J=8 Hz), 7.51 (d,2H, J=8.4 Hz), 7.29 (m, 5H), 5.11 (m, 1H), 4.88 (d, 1H, J=8.4 Hz), 3.79(m, 5H), 3.61 (m, 1H), 3.56 (s, 2H), 3.12 (m, 1H), 2.95 (d, 2H, J=13.6),2.92 and 2.87 (two m, 2H), 2.82 (dd, 1H, J=6.8 Hz, 13.6 Hz), 2.5 (m,8H), 2.37 (s, 3H), 2.1, 1.92, and 1.81 (three m, 3H), 0.88 (ABq, 6H,J=6.4 Hz).

Compound 139: To compound 135 (17 mg), AcOH (3 mg), and morpholine (9mg) in MeOH was added NaCNBH₄ (4 mg). The resulting reaction mixture wasstirred for 12 hours at room temperature. Then the reaction mixture wasdiluted with EtOAc (20 mL) and the organic layer washed with brine (2×20mL). The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated. Purification of the resulting crude product by flashsilica gel chromatography provided morpholine derivative.

The morpholine derivative (10 mg) was treated with 20% TFA(trifluoroacetic acid).CH₂Cl₂ (3 mL) for 30 min. After evaporation ofsolvent and drying the resulting amine salt, active carbonate 22 (6 mg)and Et₃N (2 equiv.) in CH₂Cl₂ (3 mL) were stirred for 3 hours at roomtemperature. Then the reaction mixture was diluted with EtOAc (20 mL)and the organic layer washed with brine (20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated. Purification ofthe resulting crude product by flash silica gel chromatography providedcompound 139. ¹H NMR (CDCl₃, 400 MHz): δ 7.75 (d, 2H, J=8 Hz), 7.5 (d,2H, J=8 Hz), 5.1 (m, 1H), 4.88 (d, 1H, J=8.4 Hz), 3.8 (m, 9H), 3.6 (m,1H), 3.55 (s, 2H), 3.14 (dd, 1H, J=7.6 Hz, 15.2 Hz), 3.05 (m, 3H), 2.91(m, 1H), 2.88 (dd, 1H, J=6.4 Hz, 13.2 Hz), 2.5 (s, 4H), 2.1, 1.9, and1.87 (three m, 3H), 0.89 (ABq, 6H, J=6.4 Hz).

IC₅₀ No. (nM) 143

3.0 144

40 145 more polar 96 145a

500 145b

>2000 145c

15 145d

4.6 146

1.8 147

60 148

185 149

20 IC₅₀ Ki No. (nM) (nM) 150

540 151

3.1 1.0 152

5.2 1.8 153

3.6 1.1 154

25 7.8 155

16 4.9 156

3.1 0.97 157

2.8 0.87 158

105 32 159

204 63 160

231 72 161

2.0 1.6 162

4.1 1.3 163

115 36 164

33 10 165

3.5 1.0 166

0.91 0.28 167

4.5 1.4 168

2.5 0.8 169

7.1 22 170

2.4 0.74 171

14 4.3 172

5.1 1.6 179

6.4 2.0 180

1500 472 181

145 45 182

4.6 1.4 183

179 56 184

1200 351 185

312 97 186

10 3.2 187

534 166 188

3.9 1.2 189

55 17 190

3.5 1.1 191

9.6 3.0 200

7.6 2.3 201

5.6 1.7 202

31 9.7 203

15 4.7 204

5.6 1.7 205

87 27 206

109 34 207

96 30 208

>2300 209

30 9.3 210

13 4.1 211

90 28 212

30 9.3 213

4.1 1.3 226

>2000 227

495 154 228

2200 638 229

9.1 2.1 230

5.3 1.6 231

8.6 2.7 232

5.4 1.7 233

8.7 2.7 234

7.3 2.3 225

8.1 2.5 225a

7.8 2.4 225b

7.8 2.4 225c

8.5 2.6 225d

5.3 1.6 225e

5.0 1.6 225f

11 3.4 225g

10 3.1 225h

6.8 2.1 225i

17 5.3 235

9.3 2.9 236

11 3.4 237

10 3.1 238

4 1.2 239

34 11 248

730 249

37 250

1.0

3S-Aminopyrrolidin-2-one (252)

A solution of (S)-4-amino-2-methylbutyric acid hydrochloride (251, 190mg, 1.23 mmol) in acetonitrile (25 mL) and hexamethyldisilazane (HMDS)(1 mL) was heated under reflux for 72 hours. The solvent was evaporatedunder vacuum, and the residue was purified by silica gel columnchromatography eluting with 15% MeOH in CHCl₃, yielding 36 mg ofcompound 252 (29%) as a colorless solid, R_(f)=0.20.

{1S-Benzyl-2R-hydroxy-3-[(3′S)-oxopyrrolidin-3-ylamino]propyl}carbamicacid tert-butyl ester (252a): A solution oftert-butyl[S-(R*,R*)]-(−)-(1-oxiranyl-2-phenylethyl)carbamate (26 mg,0.10 mmol), 3S-aminopyrrolidin-2-one (2.52, 20 mg, 0.20 mmol), andisopropylethylamine (70 μL, 0.40 mmol) in isopropanol (3 mL) was heatedunder reflux for 12 hours. The solvent was evaporated under vacuum, andthe residue was purified by silica gel column chromatography elutingwith 15% MeOH in chloroform (CHCl₃), yielding 10 mg of compound 252a(28%) as a colorless solid, R_(f)=0.25.

{1S-Benzyl-2R-hydroxy-3-[(3′S)-isobutyl(2-oxopyrrolidin-3-yl)amino]propyl}carbamicacid tert-butyl ester (252b): A solution of{1S-benzyl-2R-hydroxy-3-[(3′S)-oxopyrrolidin-3-ylamino]propyl}carbamicacid tert-butyl ester (252a, 5.0 mg, 0.014 mmol), iso-butyraldehyde(0.10 mL, 1.1 mmol), and molecular sieve (3 Å, 100 mg) in EtOH (1 mL)under argon was heated at reflux for 12 hours. The solvent wasevaporated under vacuum, and the residue was redissolved in EtOH (1 mL).Glacial acetic acid (0.10 mL) was added, followed by sodiumcyanoborohydride (30 mg, 0.048 mmol). After 30 min, saturated aq. NaHCO₃(5 mL) was added, and the mixture was extracted with CHCl₃ (3×10 mL).The organic layer was dried, evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography eluting with 5%MeOH in CHCl₃, yielding 4.9 mg of compound 252b (85%) as a colorlesssolid, R_(f)=0.22.

Compound 248: A solution of{1S-benzyl-2R-hydroxy-3-[(3′S)iso-butyl-(2-oxopyrrolidin-3-yl)-amino]propyl}carbamicacid tert-butyl ester (252b, 5.0 mg, 0.012 mmol) in 20% TFA in CH₂Cl₂ (5mL) was stirred for 30 min. The reaction mixture then was concentratedand redissolved CH₂Cl₂ (5 mL). To this solution was added triethylamine(0.1 mL), and, after 5 min, carbamate 22 (3.0 mg, 0.013 mmol). Afterstirring for 20 min, the solvent was evaporated under vacuum, and theresidue was purified by silica gel column chromatography eluting with 5%MeOH in CHCl₃, yielding 4.5 mg of compound 248 (86%) as a colorlesssolid, R_(f)=0.15. ¹H-NMR (400 MHz, CDCl₃): δ 7.29–7.17 (m, 5H), 6.05(bs, 1H), 5.10 (bs, 1H), 4.88 (d, 1H, J=9.3 Hz), 3.84–3.63 (m, 7H),3.34–3.28 (m, 2H), 2.93–2.87 (m, 2H), 2.46–2.43 (m, 2H), 2.31–2.05 (m,4H), 1.95–1.87 (m, 2H), 1.77–1.70 (m, 1H), 0.94 (d, 3H, J=6.4 Hz), 0.87(d, 3H, J=6.4 Hz.

Compound 249: A solution of{1S-benzyl-2R-hydroxy-3-[(3′S)-isobutyl(2-oxopyrrolidin-3-yl)-amino]propyl}carbamicacid tert-butyl ester (252b, 5.0 mg, 0.012 mmol) in 20% TFA in CH₂Cl₂ (5mL) was stirred for 30 min. The reaction mixture then was concentratedand redissolved CH₂Cl₂ (5 mL). To this solution was added triethylamine(0.1 mL), and, after 5 min, carbamate 15 (3.4 mg, 0.013 mmol). Afterstirring for 20 min, the solvent was evaporated under vacuum, and theresidue was purified by silica gel column chromatography eluting with 5%MeOH in CHCl₃, yielding 3.8 mg of compound 249 (67%) as a colorlesssolid, R_(f)=0.25. ¹H-NMR (400 MHz, CDCl₃): δ 7.26–7.16 (m, 5H), 5.63(d, 1H, J=5.2 Hz), 5.10 (bs, 1H), 5.00–4.97 (m, 1H), 3.98–3.92 (m, 2H),3.86–3.72 (m, 2H), 3.71–3.61 (m, 5H), 3.40–3.25 (m, 2H), 3.05–2.95 (m,1H), 2.92–2.81 (m, 1H), 2.75–2.69 (m, 1H), 2.53–2.37 (m, 2H), 2.33–2.18(m, 2H), 1.95–1.83 (m, 2H), 1.62–1.52 (m, 3H), 0.95 (d, 3H, J=6.2 Hz),0.88 (d, 3H, J=5.4 Hz).

3-Isobutylimino-1,3-dihydro-indol-2-one (245). To a stirred suspensionof isatin (5.00 g) in absolute EtOH (40 mL) was added isobutylamine (3.7mL) at 23° C. and the mixture was stirred for 4 hours. The mixture thenwas filtered, and a bright yellow solid collected and recrystallizedfrom EtOH to give 2.32 g, 34%, of bright yellow crystals. Imineformation resulted in an approximately 2:1 mixture of geometric isomers.¹H-NMR (300 MHz, CDCl₃): δ 10.05 (bs, major), 9.0 (bs, minor), 7.67 (d,J=7.2 Hz, major), 7.62 (d, J=7.2 Hz, minor), 7.34 (m, 2H), 7.04 (m, 3H),7.86 (d, J=7.8 Hz, minor), 4.19 (d, J=6.9 Hz, minor), 3.82 (d, J=6.9 Hz,major), 2.31 (m, major), 2.12 (m, minor), 1.08 (d, J=6.3 Hz, major),1.03 (d, J=6.9 Hz, minor); ¹³C-NMR (75 MHz, CDCl₃): δ 165.8, 154.6,145.0, 133.3, 132.5, 127.1, 122.9, 122.2, 117.4, 111.9, 110.5, 62.3,59.8, 30.5, 30.1, 21.0, 20.7.

3-Isobutylamino-1,3-dihydro-indol-2-one (246). To a solution of imine255 (3.0 g) in EtOAc (50 mL) was added 10% Pd/C (0.10 g), and themixture was hydrogenated under a balloon for 8 hours. The mixture wasfiltered through a pad of celite and concentrated in vacuo to afford anoff-white solid. To this solid was added 100 mL of an anhydrous diethylether-HCl solution and the mixture was shaken for 10 minutes. Theresulting light-pink colored salt was filtered and recrystallized fromEtOH-ether to give 2.2 g (61%) of3-isobutylamino-1,3-dihydro-indol-2-one hydrochloride. ¹H-NMR (300 MHz,CD₃OD): δ 7.67 (d, J=8.1 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.14 (t, J=7.8Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 5.07 (s, 1H), 3.06 (dd, J=12.0, 7.2 Hz,1H), 2.91 (dd, J=12.0, 6.9 Hz, 1H), 2.08 (m, 1H), 1.04 (d, J=1.8 Hz,3H), 1.02 (d, J=1.5 Hz, 3H); ¹³C-NMR (75 MHz, CD₃OD): δ 172.9, 144.7,132.5, 127.3, 124.2, 121.5, 11.2.1, 58.5, 53.4, 27.5, 20.4. Thehydrochloride salt was converted to the free amine immediately prior touse in the next reaction by washing with NaHCO₃ and extracting withCH₂Cl₂. ¹H-NMR (300 MHz, CDCl₃): δ 9.62 (s, 1H), 7.35 (d, J=7.5 Hz, 1H),7.21 (t, J=7.5 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H),4.39 (s, 1H), 2.41 (dd, J=10.5, 6.6 Hz), 2.20 (dd, J=10.5, 6.9 Hz), 1.67(m, 1H), 0.88 (d, J=2.4 Hz, 3H), 0.86 (d, J=2.4 Hz, 3H). Peaks at 2.41and 2.20 combined for 3H due to overlap of the NH peak; ¹³C-NMR (75 MHz,CDCl₃): δ 180.4, 141.7, 128.8, 127.6, 125.0, 122.6, 110.2, 61.0, 52.7,28.9, 20.6, 20.5.

(2R,3S)-3-[(3-Azido-2-hydroxy-4-phenyl-butyl)-isobutyl-amino]-1,3-dihydro-indol-2-one(247). To a solution of (2R,3S)-2-(1-azido-2-phenyl-ethyl)oxirane (64)(16.2 mg) in isopropanol (2 mL) was added freshly washed3-isobutylamino-1,3-dihydro-indol-2-one (15.4 mg), and the solution wasrefluxed for 22 hours. The mixture was cooled and solvent removed underreduced pressure. Flash column chromotagraphy (40, 70% EtOAc/hexane)afforded the azido alocohol (12.4 mg, 37%) as a 2:1 mixture ofdiastereomers. ¹H-NMR (300 MHz, CDCl₃): δ 7.99 (s, minor), 7.77 (s,major), 7.37 (d, J=7.8 Hz), 7.32–7.20 (m), 7.12–7.05 (m), 6.89 (t, J=7.5Hz, 2H), 4.46 (s, minor), 4.43 (s, major), 4.30 (bs, major), 4.04 (bs,minor), 3.82–3.76 (m), 3.65–3.59 (m), 3.56–3.53 (m), 3.30 (dd, J=12.9,2.4 Hz), 3.00–2.91 (m), 2.76–2.69 (m), 2.60–2.47 (m), 2.07–1.99 (m),1.84–1.80 (m), 1.59 (s, minor), 1.28–1.23 (m), 0.97–0.85 (m).

Compound 250. To a solution of azide 247 in dry THF (2 mL) was addedmixed carbonate 15 (10.0 mg), triethylamine (10 μL), and 10% Pd/C (7.6mg), and the mixture was hydrogenated under a balloon for 2 hours. Themixture was filtered through a pad of celite and the filtrateconcentrated in vacuo. The residue was chromatographed over silica gel(60, 100% EtOAc/hexane) to afford compound 250 as a white solid (10.9mg, 60%) as a mixture of diasteromers. ¹H-NMR (500 MHz, CD₃OD): δ 7.43(d, J=7.5 Hz, 1H), 7.39 (d, J=7.4 Hz), 7.25–7.13 (m), 7.04 (t, J=6.8 Hz,1H), 6.99 (t, J=7.4 Hz, 1H), 6.86 (d, J=7.8 Hz), 5.57 (t, J=4.9 Hz),4.56 (s), 4.54 (s), 3.92–3.88 (m), 3.78–3.63 (m), 3.24–3.22 (m), 3.15(dd, J=14.0, 3.6 Hz), 2.96 (dd, J=13.9, 3.6 Hz), 2.86–2.84 (m), 2.81(m), 2.77 (d, J=5.3 Hz), 2.69–2.65 (m), 2.60–2.53 (m), 2.32–2.28 (m),2.06–2.01 (m), 1.83–1.78 (m), 1.57–1.48 (m), 1.40–1.34 (m), 1.29 (s),0.93–0.84 (m).

IC₅₀ No. (nM) 253

1.0 254

1.0 255

256

1.7 257

2.9 258

3.9 259

2.8 260

261

2.2 262

263

264

265

267

268

Scheme IC₅₀ No. No. (nM)

528b 386  269

528a   3.4 270

  6.4 271

305a  3 272

305b    3.42 273

306a 17(pM) 276

309a 20(pM) 265

309b 277

401a   0.1 278

401b    0.16 279

402a    0.34 280

402b 281

403a 26(pM) 282

283

306b 14(pM)

307a  7

307b 12 274

308a   0.1 275

308b    0.37

{(1S)-Benzyl-(2R)-hydroxy-3-[(4-methoxybenzenesulfonyl)-(5-oxopyrrolidin-(2R)-ylmethyl)amino]-propyl}carbamicacid tert-butyl ester (305a)

A solution of{(1S)-benzyl-(2R)-hydroxy-3-[(5-oxopyrrolidin-(2R)-ylmethyl)amino]propyl}-carbamicacid tert-butyl ester (304a, 19.4 mg, 0.051 mmol) and4-methoxybenzenesulfonyl chloride (32.0 mg, 0.154) in CH₂Cl₂ (4 mL) andsat. aq. NaHCO₃ (4 mL) was stirred overnight at room temperature. Themixture then was extracted with CHCl₃ (3×5 mL). The organic layer wasdried over NaSO₄, and the residue was purified by silica gel columnchromatography eluting with 10% MeOH in CHCl₃, yielding 22 mg ofcompound 305a (78%) as a colorless solid, R_(f)=0.45. ¹H NMR (300 MHz,CDCl₃): δ 1.33 (s, 9H), 1.58–1.76 (m, 1H), 2.10–2.26 (m, 1H), 2.27–2.42(m, 2H), 2.73–2.83 (m, 1H), 2.84–3.07 (m, 3H), 3.19 (t, 2H, J=14.4 Hz),3.70–3.84 (m, 1H), 3.85 (s, 3H), 3.92–4.05 (m, 2H), 4.90 (bs, 1H), 6.95(d, 2H, J=9.0 Hz), 7.18–7.30 (m, 5H), 7.68 (d, 2H, J=9.0 Hz), 7.37 (bs,1H).

{(1S)-Benzyl-(2R)-hydroxy-3-[(4-nitrobenzenesulfonyl)-(5-oxopyrrolidin-(2R)-ylmethyl)amino]propyl}-carbamicacid tert-butyl ester (307a)

A solution of{(1S)-benzyl-(2R)-hydroxy-3-[(5-oxopyrrolidin-(2R)-ylmethyl)amino]propyl}carbamicacid tert-butyl ester (304a, 29.0 mg. 0.0768 mmol) and4-nitrobenzenesulfonyl chloride (51.0 mg 0.230) in CH₂Cl₂ (1 mL) andsat. aq. NaHCO₃ (1 mL) was stirred overnight at room temperature. Themixture then was extracted with CHCl₃ (3×5 mL). The organic layer wasdried over NaSO₄, and the residue was purified by silica gel columnchromatography eluting with 6% MeOH in CHCl₃, yielding 38 mg of compound307a (88%) as a colorless solid, R_(f)=0.20. ¹H NMR (400 MHz, CDCl₃): δ1.37 (s, 9H), 1.60–1.74 (m, 1H), 2.23–2.30 (m, 1H), 2.35–2.40 (m, 2H),2.88–2.93 (m, 1H), 2.94–3.08 (m, 3H), 3.36–3.42 (m, 2H), 2.67–3.84 (m,1H), 3.92–4.05 (m, 2H), 4.69 (bs, 1H), 7.20–7.33 (m, 6H), 7.96 (d, 2H,J=6.8 Hz), 8.36 (d, 2H, J=6.8 Hz).

Compound 273

A solution of{(1S)-benzyl-(2R)-hydroxy-3-[(4-methoxybenzenesulfonyl)-(5-oxopyrrolidin-(2R)-ylmethyl)amino]propyl}carbamicacid tert-butyl ester (305a, 8.2 mg, 0.0150 mmol) in 20% TFA in CH₂Cl₂(5 mL) was stirred for 30 minutes. The reaction mixture then wasconcentrated and redissolved CH₂Cl₂ (2 mL). Triethylamine (0.00104 mL)was added to this solution, and after 5 minutes carbamate 528b (5.7 mg.0.0749 mmol) was added. After stirring for 20 minutes, the solvent wasevaporated under vacuum, and the residue was purified by silica gelcolumn chromatography eluting with 5% MeOH in CH₂Cl₂, yielding 7.7 mg ofcompound 306a (83%) as a colorless solid, R_(f)=0.20. ¹H NMR (400 MHz,CDCl₃): δ 1.52–1.73 (m, 3H), 2.15–2.26 (m, 1H), 2.35–2.41 (m, 2H),2.70–2.78 (m, 1H), 2.81–3.01 (m, 3H), 3.04–3.15 (m, 1H), 3.24–3.31 (m,2H), 3.61–3.80 (m, 3H), 3.86 (s, 3H), 3.92–4.01 (m, 2H), 4.03–4.13 (m,2H), 4.97–5.02 (m, 1H), 5.60 (bs, 1H), 5.61 (d, 1H, J=5.4 Hz), 6.97 (d,2H, J=7.2 Hz), 7.19–7.26 (m, 5H), 7.70 (d, 2H, J=7.2 Hz), 7.91 (bs, 1H).

Compound 274

A solution of{(1S)-benzyl-(2R)-hydroxy-3-[(4-nitrobenzenesulfonyl)-(5-oxopyrrolidin-(2R)-yl-methyl)amino]propyl}carbamicacid tert-butyl ester (307a, 15.0 mg. 0.0267 mmol) in 20% TFA in CH₂Cl₂(5 mL) was stirred for 30 minutes. The reaction mixture then wasconcentrated and redissolved CH₂Cl₂ (2 mL). Triethylamine (0.00185 mL)was added to this solution, and after 5 minutes carbamate 28b (10.1 mg,0.0373 mmol) was added. After stirring for 20 minutes, the solvent wasevaporated under vacuum, and the residue was purified by silica gelcolumn chromatography eluting with 6% CH₂Cl₂ in CHCl₃, yielding 13.3 mgof compound 308a (81%) as a colorless solid, R_(f)=0.19. ¹H NMR (500MHz, CDCl₃): δ 1.59–1.69 (m, 2H), 1.70–1.80 (m, 1H), 2.18–2.28 (m, 1H),2.34–2.41 (m, 2H), 2.70–2.77 (m, 1H), 2.88–2.93 (m, 1H), 3.03–3.16 (m,3H), 3.22–3.28 (m, 2H), 3.60–3.69 (m, 1H), 3.71–3.76 (m, 1H), 3.78–3.83(m, 1H), 3.91–3.99 (m, 2H), 4.00–4.12 (m, 2H), 4.99–5.04 (m, 1H), 5.57(bs, 1H), 5.63 (d, 1H, J=5.2 Hz), 7.19–7.28 (m, 5H), 7.95 (d, 2H, J=8.8Hz), 8.14 (bs, 1H), 8.36 (d, 2H, J=8.8 Hz).

Compound 276

A solution of compound 308a (20 mg, 0.032 mmol), zinc (65 mg, 0.99mmol), calcium chloride (CaCl₂) (2.5 mg, 0.023) in ethanol (EtOH) (4mL), and water (1 mL) were refluxed for 5.5 hours. Sat. aq. NaHCO₃ wasadded to this mixture (5 mL), then the reaction mixture was extractedwith CHCl₃ (3×5 mL). The organic layer was dried over NaSO₄, and theresidue was purified by silica gel column chromatography eluting with10% MeOH in CHCl₃, yielding 9.0 mg of compound 309a (47%) as a colorlesssolid, R_(f)=0.24. ¹H NMR (400 MHz, CDCl₃): δ 1.60–1.69 (m, 2H),1.73–1.81 (m, 1H), 2.15–2.16 (m, 1H), 2.31–2.41 (m, 2H), 2.60–2.71 (m,2H), 2.72–2.93 (m, 2H), 3.07–3.11 (m, 1H), 3.22–3.35 (m, 2H), 3.60–3.72(m, 2H), 3.81–3.99 (m, 4H), 4.00–4.05 (m, 1H), 4.97–5.03 (m, 1H), 5.35(bs, 1H), 5.63 (d, 1H, J=5.2 Hz), 6.66 (d, 2H, J=11.2 Hz), 8.14 (bs,1H), 7.19–7.28 (m, 5H), 7.53 (d, 2H, J=11.2 Hz)

Compound 277

A solution of{(1S)-benzyl-(2R)-hydroxy-3-[(4-methoxybenzenesulfonyl)-(5-oxopyrrolidin-(2R)-ylmethyl)amino]propyl}carbamicacid tert-butyl ester (305a, 11.0 mg, 0.0201 mmol) in 20% TFA in CH₂Cl₂(5 mL) was stirred for 30 minutes. The reaction mixture then wasconcentrated and redissolved CH₂Cl₂ (2 mL). Triethylamine (0.00084 mL)was added to this solution, and after 5 minutes compound 40 (6.5 mg,0.024 mmol) was added. After stirring for 20 minutes, the solvent wasevaporated under vacuum, and the residue was purified by silica gelcolumn chromatography eluting with 5% MeOH in CHCl₃, yielding 6.5 mg ofcompound 401a (54%) as a colorless solid, R_(f)=0.22. ¹H NMR (400 MHz)CDCl₃): δ 1.46–1.56 (m, 1H), 1.59–1.67 (m, 2H), 1.93–2.08 (m, 3H),2.18–2.25 (m, 2H), 2.28–2.41 (m, 3H), 2.60–2.72 (m, 2H), 2.95–3.22 (m,5H), 3.54–3.60 (m, 1H), 3.80–3.87 (m, 3H), 3.88 (s, 3H), 3.92–4.00 (m,1H), 4.35–4.41 (m, 1H), 4.92 (bs, 1H), 5.33 (m, 1H), 6.99 (d, 2H, J=8.8Hz), 7.18–7.29 (m, 5H), 7.71 (d, 2H, J=8.8 Hz).

Compound 279

A solution of{(1S)-benzyl-(2R)-hydroxy-3-[(4-nitrobenzenesulfonyl)-(5-oxopyrrolidin-(2R)-yl-methyl)amino]propyl}carbamicacid tert-butyl ester (307a, 19.0 mg, 0.0337 mmol) in 20% TFA in CH₂Cl₂(5 mL) was stirred for 30 minutes. The reaction mixture then wasconcentrated and redissolved CH₂Cl₂ (2 mL). Triethylamine (0.00091 mL)was added to this solution, and after 5 minutes compound 400 (12.0 mg,0.0439 mmol) was added. After stirring for 20 minutes, the solvent wasevaporated under vacuum, and the residue was purified by silica gelcolumn chromatography eluting with 5% MeOH in CHCl₃, yielding 16.8 mg of402a (81%) as a colorless solid, R_(f)=0.21. ¹H NMR (400 MHz, CDCl₃): δ1.44–1.53 (m, 1H), 1.56–1.62 (m, 2H), 1.90–2.06 (m, 5H), 2.18–2.24 (m,1H), 2.28–2.41 (m, 2H), 2.60–2.69 (m, 1H), 2.70–2.78 (m, 1H), 2.99–3.22(m, 4H), 3.23–3.35 (m, 1H), 3.54–3.62 (m, 1H), 3.80–3.90 (m, 3H),3.95–4.02 (m, 1H), 4.31–4.40 (m, 1H), 4.91 (bs, 1H), 5.22 (m, 1H),7.20–7.30 (m, 5H), 7.98 (d, 2H, J=8.7 Hz), 8.36 (d, 2H, J=8.7 Hz).

(5R)-Hydroxymethylpyrrolidin-2-one (302a)

To 5-oxopyrrolidine-(2R)-carboxylic acid (301a, 5.00 g, 38.7 mmol) inMeOH (50 mL) and DMF (0.5 mL) was added SOCl₂ (3.4 mL, 45.5 mmol)dropwise at 0° C. After stirring overnight, the solvent was evaporatedunder vacuum, CHCl₃ (70 mL) and saturated aq. NaHCO₃ (30 mL) were added;and the mixture was extracted with CHCl₃ (3×10 mL). The organic layerwas dried over NaSO₄. Distillation under vacuum (1 mm) gave 3.35 g (60%)of 5-oxopyrrolidine-(2R)-carboxylic acid methyl ester, bp. 140° C.Sodium borohydride (44.28 mmol) at 0° C. was added to this ester (3.17g, 22.14 mmol) in EtOH (75 mL). After stirring overnight, the reactionmixture was quenched with sat. aq. NH₄Cl solution. The white precipitatewas filtered, and the residue was washed with ethyl acetate (EtOAc).Evaporation of the solvent gave 2.30 g (90%) of compound 302a, which wasused without further purification. ¹H NMR (300 MHz, CDCl₃): δ 1.67–1.79(m, 1H), 2.03–2.12 (m, 1H), 2.15–2.35 (m, 2H), 3.35–3.43 (m, 1H),3.56–3.62 (m, 1H), 3.69–3.77 (m, 1H), 4.81 (bs, 1H), 7.55 (bs, 1H).

(5R)-Aminomethylpyrrolidine-2-one (303a)

To a solution of (5R)-hydroxymethyl-pyrrolidin-2-one (302a, 0.800 g,6.96 mmol) and Et₃N (1.94 mL, 13.91 mmol) in CH₂Cl₂ (40 ml) at 0° C. wasadded MsCl (0.591 mL, 7.65 mmol). After stirring overnight, CHCl₃ (70mL) and saturated aq. NaHCO₃ (30 mL) were added, and the mixture wasextracted with CHCl₃ (6×20 mL) and EtOAc (6×20 mL). The organic layerwas dried over NaSO₄, and the residue was purified by silica gel columnchromatography by eluting with 7% MeOH in CHCl₃, yielding 864 mg of thecorresponding mesylate (65%) as a colorless solid, R_(f)=0.21. Asolution of this mesylate (0.306 g, 1.60 mmol) and NaN₃ (0.208 g, 3.20mmol) in DMF (5 mL) was stirred for 6 h at 80° C. Then the solvent wasremoved, and the residue was purified by silica gel columnchromatography eluting with 8% MeOH in CHCl₃, yielding 236 mg ofcorresponding azide (98%) as a colorless solid, R_(f)=0.30. A solutionof this azide (72.5 mg, 0.518 mmol) in EtOAc (10 mL) was hydrogenatedwith Pd/C (10%) at 20 psi for 4 hours. Filtration through a pad ofsilica gel (5 g) with MeOH (50 mL) gave 53 mg of compound 303a (90%). ¹HNMR (300 MHz, CDCl₃): δ 1.64–1.71 (m, 1H), 2.11–2.19 (m, 1H), 2.20–2.27(m, 2H), 2.57–2.64 (m, 1H), 2.65–2.77 (m, 1H), 2.81 (bs, 2H), 3.63–3.67(m, 1H), 7.59 (bs, 1H).

{(1S)-Benzyl-(2R)-hydroxy-3-[(5-oxopyrrolidin-(2R)-ylmethyl)amino]propyl}carbamicacid tert-butyl ester (304a)

A solution of tert-butyl[S—(R*,R*)]-(−)-(1-oxiranyl-2-phenylethyl)carbamate (2, 65.0 mg, 0.247mmol), (5R)-aminomethylpyrrolidin-2-one (303a, 120 mg, 0.105 mmol), anddiisopropylethylamine ((iPr)₂EtN) (0.200 mL, 1.15 mmol) in isopropanol(10 mL) was heated under stirring at 70° C. for 14 hours. The solventwas evaporated under vacuum, and the residue was purified by silica gelcolumn chromatography eluting with 15% MeOH in CHCl₃, yielding 71 mg ofcompound 272 (76%) as a colorless solid, R_(f)=0.22. ¹H NMR (400 MHz,CDCl₃): δ 1.34 (s, 9H), 1.63–1.78 (m, 1H), 2.12–2.28 (m, 1H), 2.29–2.38(m, 2H), 2.53–2.63 (m, 1H), 2.64–2.73 (m, 1H), 2.74–2.86 (m, 2H),2.92–3.00 (m, 2H), 3.52–3.59 (m, 1H), 3.72–3.90 (m, 2H), 4.88 (d, 1H,J=9.0 Hz), 7.18–7.22 (m, 3H), 7.26–7.30 (m, 2H), 7.42 (bs, 1H).

Compound 281

A solution of compound 402a (15.0 mg, 0.024 mmol), zinc (50 mg, 0.77mmol), CaCl₂ (2.0 mg, 0.018) in EtOH (1.5 mL), and water (0.5 mL) wasrefluxed for 4 hours. Sat. aq. NaHCO₃ (5 mL) was added to this mixture,then the mixture was extracted with CHCl₃ (3×5 mL). The organic layerwas dried over Na₂SO₄, and the residue was purified by silica gel columnchromatography eluting with 10% MeOH in CHCl₃, yielding 8.0 mg ofcompound 403a (57%) as a colorless solid, R_(f)=0.23. ¹H NMR (400 MHz,CDCl₃): δ 149–1.56 (m, 1H), 1.59–1.64 (m, 2H), 1.83–1.92 (m, 3H),1.93–2.05 (m, 2H), 2.15–2.27 (m, 1H), 2.30–2.41 (m, 2H), 2.58–2.65 (m,1H), 2.65–2.73 (m, 1H), 2.95–3.03 (m, 1H), 3.04–3.20 (m, 4H), 3.53–3.62(m, 1H), 3.78–3.88 (m, 3H), 3.92–4.0 (m, 1H), 4.35–4.41 (m, 1H), 4.92(bs, 1H), 5.38 (m, 1H), 6.67 (d, 2H, J=8.7 Hz), 7.26–7.36 (m, 5H), 7.54(d, 2H, J=8.7 Hz).

Compounds 284 and 285

For compounds 284 and 285, R^(f) is defined as hydro or C₁₋₆alkyl.Preferably, R^(f) is hydro, methyl, or ethyl. Compounds 284 and 285 wereprepared by the methods described above. The ligand

was prepared by the method disclosed in A. D. Rao et al., J. IndianChem. Soc., 62:3, pages 234–237 (1985).

Obviously, many modifications and variations of the invention ashereinbefore set forth can be made without departing from the spirit andscope thereof, and, therefore, only such limitations should be imposedas are indicated by the appended claims.

1. A compound having a formula

wherein R¹ is

R² is selected from the group consisting of

R³ is

X is selected from the group consisting of O, NR^(e), and S; R^(d) isselected from the group consisting of C₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneC₃₋₈heterocycloalkyl, OR^(e), C₁₋₃alkyleneOR^(e), N(R^(e))₂,SR^(e), halo, nitro, CHO, cyano, NC, C(═O)R^(e), OC(═O)R^(e),C(═O)OR^(e), C(═O)N(R^(e))₂, CH═NOH, CH═CHCH₂OH, N(R^(e))COR^(e), andC₁₋₃alkyleneN(R^(e))₂, or two R^(d) groups are taken together to form afive-, six-, or seven-mernbered aliphatic ring optionally containing oneor two of the moiety X; R^(e) is selected from the group consisting ofhydro, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl, C₁₋₈cycloalkyl, THP,Ts, Boc, and C₃₋₈heterocycloalkyl; q is 0 through 3; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein R¹ is


3. The compound of claim 1 wherein R² is selected from the groupconsisting of


4. The compound of claim 1 wherein R² is selected from the groupconsisting of


5. The compound of claim 2 wherein R^(d), independently, is selectedfrom the group consisting of CH₂OH, NH₂, OH, CH₃, CH₂CH₃, CH₂NH₂, CHO,Cl, F, nitro, OTHP, OCH₃, CH₂NHCH₃, CH═N—OH, and CH₂OCH₃, or two R^(d)groups are taken together with the carbons to which they are attached toform


6. The compound of claim 1 wherein said compound has an IC₅₀ value vs.HIV-1 protease of less than about 500 nM.
 7. The compound of claim 6wherein said compound has an IC₅₀ value vs. HIV-1 protease of less thanabout 20 nM.
 8. A compound of claim 1 selected from the group consistingof


9. A compound having a formula


10. A compound having a formula

wherein R¹ is

R² is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneN(R^(e))₂, heterocycloalkyl, —NH₂, —NHBoc,C₁₋₃alkyleneheterocycloalkyl,

optionally substituted with oxo(═O),

optionally substituted with oxo,

optionally substituted with oxo,

R³ is selected from the group consisting of

X is selected from the group consisting of O, NR^(e), and S; C is afive- or six-mernbered aliphatic ring containing one to three of themoiety X, and optionally substituted with oxo; R^(b) and R^(c),independently, are selected from the group consisting of hydro, OH,C₁₋₃alkyl, C₁₋₃alkyleneOH, and C₁₋₃alkyleneN(R^(e))₂, or R^(b) and R^(c)are taken together to form a five-, six-, or seven-membered aliphaticring optionally containing one or two of the moiety X; R^(d) is selectedfrom the group consisting of C₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneC₃₋₈heterocycloalkyl, OR^(e), C₁₋₃alkyleneOR^(e), N(R^(e))₂,SR^(e), halo, nitro, CHO, cyano, NC, C(═O)R^(e), OC(O)R^(e),C(═O)OR^(e), C(═O)N(R^(e))₂, CH═NOH, CH═CHCH₂OH, N(R^(e))COR^(e), andC₁₋₃alkyleneN(R^(e))₂, or two R^(d) groups are taken together to form afive-, six-, or seven-membered aliphatic ring optionally containing oneor two of the moiety X; R^(e) is selected from the group consisting ofhydro, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl, C₃₋₈cycloalkyl, THP,Ts, Boc, and C₃₋₈heterocycloalkyl; q is 0 through 3; or apharmaceutically acceptable salt thereof.
 11. A compound having aformula

wherein R¹ is selected from the group consisting of C₁₋₆alkyl, aryl,C₁₋₃alkyleneheteroaryl,

R² is selected from the group consisting of

R³ is selected from the group consisting of

X is selected from the group consisting of O, NR^(e), S, SO, and SO₂; Aand B, independently, are a five-, six-, or seven-membered aliphaticring, wherein at least one ring contains one or two of the moiety X; Cis a five- or six-membered aliphatic ring containing one to three of themoiety X, and optionally substituted with oxo; R^(b) and R^(c),independently, are selected from the group consisting of hydro, OH,C₁₋₃alkyl, C₁₋₃alkyleneOH, and C₁₋₃alkyleneN(R^(e))₂, or R^(b) and R^(c)are taken together to form a five-, six-, or seven-membered aliphaticring optionally containing one or two of the moiety X; R^(d) is selectedfrom the group consisting of C₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₃alkyleneC₃₋₈heterocycloalkyl, OR^(e), C₁₋₃alkyleneOR^(e), N(R^(e))₂,SR^(e), halo, nitro, CRO, cyano, NC, C(═O)R^(e), OC(═O)R^(e),C(═0)OR^(e), C(═O)N(R^(e))₂, CH═NOH, CH═CHCH₂OH, N(R^(e))COR^(e), andC₁₋₃alkyleneN(R^(e))₂, or two R^(d) groups are taken together to form afive-, six-, or seven-membered aliphatic ring optionally containing oneor two of the moiety X; R^(e) is selected from the group consisting ofhydro, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl, C₃₋₈cycloalkyl, THP,Ts, Boc, and C₃₋₈heterocycloalkyl; q is 0 through 3; or apharmaceutically acceptable salt thereof.
 12. A composition comprising acompound of claim 1 and a pharmaceutically acceptable diluent orcarrier.
 13. A method of treating a male or female mammal suffering fromHIV or AIDS wherein inhibition of HIV-1 protease provides a therapeuticbenefit comprising administering to said mammal a therapeuticallyeffective amount of a compound of claim
 1. 14. The method of claim 13wherein the mammal is a human.
 15. A method of treating a male or femalemammal suffering from HIV or AIDS wherein inhibition of HIV-1 proteaseprovides a therapeutic benefit comprising administering to said mammalan effective amount of a pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable diluent orcarrier.
 16. A method of treating a male or female mammal suffering fromwhere HIV or AIDS wherein inhibition of HIV-1 protease provides atherapeutic benefit comprising administering a therapeutically effectiveamount of (a) a compound of claim 1, and (b) a second therapeuticallyactive ingredient effective against HIV or AIDS.
 17. The method of claim16 wherein (a) and (b) are administered simultaneously, separately, orsequentially.
 18. The method of claim 16 wherein the secondtherapeutically active agent is selected from the group consisting of asecond HIV protease inhibitor, an antiviral agent, an immunomodulator, anucleoside analog, a tat antagonist, a glycosidase inhibitor, andmixtures thereof.
 19. The method of claim 18 wherein the secondtherapeutically active ingredient is selected from the group consistingof Ro 31-859, KNI-272, AZT, DDI, DDC, 3TC, D4T, PMEA, Ro 5-3335, Ro24-7429, indinavir, ritonavir, saquinavir, nelfinavir, amprenavir,abacavir, castanospremine, castanospermine 6-butryl ester,N-butyl-1-deoxynojirimycin, N-butyl-1-deoxynojirimycin per-butryl ester,097, acemannan, acyclovir, AD-439, AD5-519, adefovir clipivoxil, AL-721,alpha interferon, ansamycin, beta-fluoro-ddA, BMS-232623, BMS-234475,CI-1012, cidofovir, delaviridine, EL-10, efaviren, famciclovir, FTC,hypericin, Compound Q, ISIS 2922, lobucavir, nevirapine, novapren,peptide T, octapeptide, PNU-140690, probacol, stavudine, valacicbovir,virazole, zalcitabine, ABT-378, bropirimine, gamma interferon,interleukin-2, TNF, etanercept, infliximab, fluconalzole, piritrexim,trimetrexate, daunorubicin, leukotriene B4 receptor antagonist, andanalogs and prodrugs thereof.